357 results on '"Shannon N. Westin"'
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2. Author Correction: Distinct molecular and immune hallmarks of inflammatory arthritis induced by immune checkpoint inhibitors for cancer therapy
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Sang T. Kim, Yanshuo Chu, Mercy Misoi, Maria E. Suarez-Almazor, Jean H. Tayar, Huifang Lu, Maryam Buni, Jordan Kramer, Emma Rodriguez, Zulekha Hussain, Sattva S. Neelapu, Jennifer Wang, Amishi Y. Shah, Nizar M. Tannir, Matthew T. Campbell, Don L. Gibbons, Tina Cascone, Charles Lu, George R. Blumenschein, Mehmet Altan, Bora Lim, Vincente Valero, Monica E. Loghin, Janet Tu, Shannon N. Westin, Aung Naing, Guillermo Garcia-Manero, Noha Abdel-Wahab, Hussein A. Tawbi, Patrick Hwu, Isabella C. Glitza Oliva, Michael A. Davies, Sapna P. Patel, Jun Zou, Andrew Futreal, Adi Diab, Linghua Wang, and Roza Nurieva
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Science - Published
- 2024
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3. Predictors of Oncologic Outcome in Patients Receiving Phase I Investigational Therapy for Recurrent or Metastatic Cervical Cancer
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Ji Son, Heather Y. Lin, Siqing Fu, Amadeo B. Biter, Ecaterina E. Dumbrava, Daniel D. Karp, Aung Naing, Shubham Pant, Sarina A. Piha-Paul, Jordi Rodon, Vivek Subbiah, Apostolia M. Tsimberidou, Timothy A. Yap, Michael M. Frumovitz, Amir A. Jazaeri, Pedro T. Ramirez, Shannon N. Westin, Ying Yuan, Funda Meric-Bernstam, and David S. Hong
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phase i trial prognosis ,recurrent cervical cancer ,metastatic cervical cancer ,lymphopenia ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Introduction: We aimed to identify clinical, pathologic, and treatment factors that are predictive of response and survival in patients with cervical cancer referred to phase I clinical trials. Methods: Patients with cervical cancer who received at least one dose of a phase I investigational agent at our institution between 2014 and 2022 were included. The log-rank test was used to analyze differences in progression-free survival (PFS) and overall survival (OS), and multivariable regression analysis was performed. Results: We included 65 patients with a median age of 41 years (range, 20–74), 3 prior therapies (range, 1–7), and 67.7% squamous carcinoma. The rate of distant metastasis at trial entry was 84.6%. The most common molecular alterations included PIK3CA (46.5%), PD-L1+ (46.2%), EPH (30.0%), and CREBBP (23.1%); 23.1% had received a prior checkpoint inhibitor. Phase I trials were for immunotherapy (58.5%) or targeted therapy (41.5%). The rate of biomarker matching was 21.5%. For all patients, median PFS was 3.6 months (95% CI, 2.0–5.2) and OS was 9.3 months (95% CI, 7.0–10.6). Factors at study entry associated with worse survival were presence of bone metastasis (PFS 1.6 vs 4.4 months: hazard ratio [HR], 2.8; p = 0.001; OS 3.8 vs 10.0 months: HR, 3.9; p < 0.0001) and absolute lymphocyte count below 1000/μL (PFS 1.8 vs 5.2 months: HR, 2.9; p = 0.0004; OS 7.0 vs 10.6 months: HR, 3.2; p = 0.0009). Factors associated only with worse OS were absolute neutrophil count above 4700/μL, hemoglobin below 10.5 g/dL, and smoking status. Grade 3+ treatment-related adverse events were seen in 16.9% of cases. Conclusion: Bone metastasis and absolute lymphocyte count below normal range at phase I study entry portend poor survival in patients with recurrent or metastatic cervical cancer.
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- 2023
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4. EphA2- and HDAC-Targeted Combination Therapy in Endometrial Cancer
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Robiya Joseph, Santosh K. Dasari, Sujanitha Umamaheswaran, Lingegowda S. Mangala, Emine Bayraktar, Cristian Rodriguez-Aguayo, Yutuan Wu, Nghi Nguyen, Reid T. Powell, Mary Sobieski, Yuan Liu, Mark Seungwook Kim, Sara Corvigno, Katherine Foster, Pahul Hanjra, Thanh Chung Vu, Mamur A. Chowdhury, Paola Amero, Clifford Stephan, Gabriel Lopez-Berestein, Shannon N. Westin, and Anil K. Sood
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endometrial cancer ,EphA2 ,histone deacetylase ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Endometrial cancer is the most frequent malignant tumor of the female reproductive tract but lacks effective therapy. EphA2, a receptor tyrosine kinase, is overexpressed by various cancers including endometrial cancer and is associated with poor clinical outcomes. In preclinical models, EphA2-targeted drugs had modest efficacy. To discover potential synergistic partners for EphA2-targeted drugs, we performed a high-throughput drug screen and identified panobinostat, a histone deacetylase inhibitor, as a candidate. We hypothesized that combination therapy with an EphA2 inhibitor and panobinostat leads to synergistic cell death. Indeed, we found that the combination enhanced DNA damage, increased apoptosis, and decreased clonogenic survival in Ishikawa and Hec1A endometrial cancer cells and significantly reduced tumor burden in mouse models of endometrial carcinoma. Upon RNA sequencing, the combination was associated with downregulation of cell survival pathways, including senescence, cyclins, and cell cycle regulators. The Axl-PI3K-Akt-mTOR pathway was also decreased by combination therapy. Together, our results highlight EphA2 and histone deacetylase as promising therapeutic targets for endometrial cancer.
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- 2024
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5. Exploiting metabolic vulnerabilities after anti-VEGF antibody therapy in ovarian cancer
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Deanna Glassman, Mark S. Kim, Meredith Spradlin, Sunil Badal, Mana Taki, Pratip Bhattacharya, Prasanta Dutta, Charles V. Kingsley, Katherine I. Foster, Olamide Animasahun, Jin Heon Jeon, Abhinav Achreja, Anusha Jayaraman, Praveen Kumar, Minal Nenwani, Fulei Wuchu, Emine Bayraktar, Yutuan Wu, Elaine Stur, Lingegowda Mangala, Sanghoon Lee, Timothy A. Yap, Shannon N. Westin, Livia S. Eberlin, Deepak Nagrath, and Anil K. Sood
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Oncology ,Cellular physiology ,Cancer ,Science - Abstract
Summary: Despite modest clinical improvement with anti-vascular endothelial growth factor antibody (AVA) therapy in ovarian cancer, adaptive resistance is ubiquitous and additional options are limited. A dependence on glutamine metabolism, via the enzyme glutaminase (GLS), is a known mechanism of adaptive resistance and we aimed to investigate the utility of a GLS inhibitor (GLSi). Our in vitro findings demonstrated increased glutamine abundance and a significant cytotoxic effect in AVA-resistant tumors when GLSi was administered in combination with bevacizumab. In vivo, GLSi led to a reduction in tumor growth as monotherapy and when combined with AVA. Furthermore, GLSi initiated after the emergence of resistance to AVA therapy resulted in a decreased metabolic conversion of pyruvate to lactate as assessed by hyperpolarized magnetic resonance spectroscopy and demonstrated robust antitumor effects with a survival advantage. Given the increasing population of patients receiving AVA therapy, these findings justify further development of GLSi in AVA resistance.
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- 2023
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6. Distinct molecular and immune hallmarks of inflammatory arthritis induced by immune checkpoint inhibitors for cancer therapy
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Sang T. Kim, Yanshuo Chu, Mercy Misoi, Maria E. Suarez-Almazor, Jean H. Tayar, Huifang Lu, Maryam Buni, Jordan Kramer, Emma Rodriguez, Zulekha Hussain, Sattva S. Neelapu, Jennifer Wang, Amishi Y. Shah, Nizar M. Tannir, Matthew T. Campbell, Don L. Gibbons, Tina Cascone, Charles Lu, George R. Blumenschein, Mehmet Altan, Bora Lim, Vincente Valero, Monica E. Loghin, Janet Tu, Shannon N. Westin, Aung Naing, Guillermo Garcia-Manero, Noha Abdel-Wahab, Hussein A. Tawbi, Patrick Hwu, Isabella C. Glitza Oliva, Michael A. Davies, Sapna P. Patel, Jun Zou, Andrew Futreal, Adi Diab, Linghua Wang, and Roza Nurieva
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Science - Abstract
Abstract Immune checkpoint inhibitors are associated with immune-related adverse events (irAEs), including arthritis (arthritis-irAE). Management of arthritis-irAE is challenging because immunomodulatory therapy for arthritis should not impede antitumor immunity. Understanding of the mechanisms of arthritis-irAE is critical to overcome this challenge, but the pathophysiology remains unknown. Here, we comprehensively analyze peripheral blood and/or synovial fluid samples from 20 patients with arthritis-irAE, and unmask a prominent Th1-CD8+ T cell axis in both blood and inflamed joints. CX3CR1hi CD8+ T cells in blood and CXCR3hi CD8+ T cells in synovial fluid, the most clonally expanded T cells, significantly share TCR repertoires. The migration of blood CX3CR1hi CD8+ T cells into joints is possibly mediated by CXCL9/10/11/16 expressed by myeloid cells. Furthermore, arthritis after combined CTLA-4 and PD-1 inhibitor therapy preferentially has enhanced Th17 and transient Th1/Th17 cell signatures. Our data provide insights into the mechanisms, predictive biomarkers, and therapeutic targets for arthritis-irAE.
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- 2022
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7. Combination of EphA2- and Wee1-Targeted Therapies in Endometrial Cancer
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Santosh K. Dasari, Robiya Joseph, Sujanitha Umamaheswaran, Lingegowda S. Mangala, Emine Bayraktar, Cristian Rodriguez-Aguayo, Yutuan Wu, Nghi Nguyen, Reid T. Powell, Mary Sobieski, Yuan Liu, Mamur A. Chowdhury, Paola Amero, Clifford Stephan, Gabriel Lopez-Berestein, Shannon N. Westin, and Anil K. Sood
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endometrial cancer ,EphA2 ,Wee1 ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
EphA2 tyrosine kinase is upregulated in many cancers and correlated with poor survival of patients, including those with endometrial cancer. EphA2-targeted drugs have shown modest clinical benefit. To improve the therapeutic response to such drugs, we performed a high-throughput chemical screen to discover novel synergistic partners for EphA2-targeted therapeutics. Our screen identified the Wee1 kinase inhibitor, MK1775, as a synergistic partner to EphA2, and this finding was confirmed using both in vitro and in vivo experiments. We hypothesized that Wee1 inhibition would sensitize cells to EphA2-targeted therapy. Combination treatment decreased cell viability, induced apoptosis, and reduced clonogenic potential in endometrial cancer cell lines. In vivo Hec1A and Ishikawa-Luc orthotopic mouse models of endometrial cancer showed greater anti-tumor responses to combination treatment than to either monotherapy. RNASeq analysis highlighted reduced cell proliferation and defective DNA damage response pathways as potential mediators of the combination’s effects. In conclusion, our preclinical findings indicate that Wee1 inhibition can enhance the response to EphA2-targeted therapeutics in endometrial cancer; this strategy thus warrants further development.
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- 2023
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8. A phase II study of MK-2206, an AKT inhibitor, in uterine serous carcinoma
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Elizabeth H. Stover, Niya Xiong, Andrea P. Myers, Nabihah Tayob, Victoria Engvold, Madeline Polak, Russell R. Broaddus, Vicky Makker, Ronny Drapkin, Joyce F. Liu, Neil S. Horowitz, Funda Meric-Bernstam, Carol Aghajanian, Robert L. Coleman, Gordon B. Mills, Lewis C. Cantley, Ursula A. Matulonis, Shannon N. Westin, and Panagiotis A. Konstantinopoulos
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Uterine serous carcinoma ,MK-2206 ,AKT inhibitor ,PI3K/AKT pathway ,Gynecology and obstetrics ,RG1-991 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Uterine serous carcinoma (USC) is an uncommon subtype of endometrial cancer with a poor prognosis. USCs have genomic alterations in the PI3K pathway. A prior phase II study of AKT inhibitor MK-2206 (an allosteric AKT inhibitor, primarily affecting AKT1 and AKT2) in endometrial cancers resulted in progression-free survival (PFS) of ≥6 months in five out of seven patients with USC. To further assess the activity of MK-2206 in USC, we designed a phase II, single-stage assessment of MK-2206 in patients with advanced or recurrent high-grade serous endometrial cancer, who had received up to two lines of prior therapy. MK-2206 (135 mg) was administered orally once per week, in continuous 28-day cycles. Fourteen patients received treatment. The most common treatment-related adverse events were diarrhea (36%), acneiform rash (36%), nausea (29%), fatigue (29%), and hyperglycemia (21%); most events were grade 1–2. One confirmed partial response was observed in a patient who was also alive and progression-free at 6 months. One additional patient was alive and progression-free at 6 months. The clinical benefit rate was 14.3% (95% CI: 1.8 to 42.8). Five patients had stable disease (35.7%) and seven had progressive disease (50%); one was unevaluable. Median PFS was 2 months (95% CI: 1.6 to 4.4) and median overall survival was 6.4 months (95% CI: 5.1 to not reached). In summary, MK-2206 had limited activity in USC, although a few patients achieved sustained progression-free intervals in this study and in the previously reported phase II trial of MK-2206. Further investigations are needed to identify features associated with response.
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- 2022
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9. Fertility-sparing treatment in early endometrial cancer: current state and future strategies
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Andreas Obermair, Eva Baxter, Donal J. Brennan, Jessica N. McAlpine, Jennifer J. Muellerer, Frédéric Amant, Mignon D. J. M. van Gent, Robert L. Coleman, Shannon N. Westin, Melinda S. Yates, Camilla Krakstad, and Monika Janda
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endometrial cancer ,fertility preservation ,conservative treatment ,progestin ,Gynecology and obstetrics ,RG1-991 - Abstract
Endometrial cancer (EC) is the fifth most common cancer in women worldwide. Global estimates show rising incidence rates in both developed and developing countries. Most women are diagnosed postmenopausal, but 14–25% of patients are premenopausal and 5% are under 40 years of age. Established risk factors include age and hyperestrogenic status associated with nulliparity, obesity, and metabolic syndrome. Standard treatment for EC, which involves total hysterectomy and bilateral salpingo-oophorectomy, has excellent survival outcomes, particularly for low-grade endometrioid tumors. However, it leads to permanent loss of fertility among women who wish to preserve their reproductive potential. With current trends of reproductive-age women delaying childbearing, rising EC incidence rates, and a growing epidemic of obesity, particularly in developed countries, research on conservative non-surgical treatment approaches remains a top priority. Fertility-sparing treatment predominantly involves the use of oral progestins and levonorgestrel-releasing intrauterine devices, which have been shown to be feasible and safe in women with early stage EC and minimal or no myometrial invasion. However, data on the efficacy and safety of conservative management strategies are primarily based on retrospective studies. Randomized clinical trials in younger women and high-risk obese patients are currently underway. Here, we have presented a comprehensive review of the current literature on conservative, fertility-sparing approaches, defining the optimal candidates and evaluating tumor characteristics, reproductive and oncologic outcomes, and ongoing clinical trials. We have also summarized current guidelines and recommendations based on the published literature.
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- 2020
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10. Phase I study of the PARP inhibitor talazoparib with radiation therapy for locally recurrent gynecologic cancers
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David S. Lakomy, Diana L. Urbauer, Shannon N. Westin, and Lilie L. Lin
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Medical physics. Medical radiology. Nuclear medicine ,R895-920 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Summary: PARP inhibitors have been shown to radiosensitize tumor cells in both in vitro and in vivo studies. This is a phase I study that aims to determine the safety, tolerability, and maximally tolerated dose of talazoparib, a PARP inhibitor, when delivered concurrently with radiotherapy in women with recurrent gynecologic cancers. Keywords: Talazoparib, Gynecologic cancer, Poly (ADP-ribose) polymerase, Radiotherapy, Dose escalation, Radiosensitizer, PARP-inhibitors
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- 2020
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11. Molecular Profiles of Serum-Derived Extracellular Vesicles in High-Grade Serous Ovarian Cancer
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Li Zhao, Sara Corvigno, Shaolin Ma, Joseph Celestino, Nicole D. Fleming, Richard A. Hajek, Adrian Lankenau Ahumada, Nicholas B. Jennings, Erika J. Thompson, Hongli Tang, Shannon N. Westin, Amir A. Jazaeri, Jianhua Zhang, P. Andrew Futreal, Anil K. Sood, and Sanghoon Lee
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extracellular vesicle ,high-grade serous ovarian cancer ,whole-genome sequencing ,RNA sequencing ,chemotherapy response ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Patients with high-grade serous ovarian cancer (HGSC) who have no visible residual disease (R0) after primary surgery have the best clinical outcomes, followed by patients who undergo neoadjuvant chemotherapy (NACT) and have a response enabling interval cytoreductive surgery. Clinically useful biomarkers for predicting these outcomes are still lacking. Extracellular vesicles (EVs) have been recognized as liquid biopsy-based biomarkers for early cancer detection and disease surveillance in other disease settings. In this study, we performed extensive molecular characterization of serum-derived EVs and correlated the findings with therapeutic outcomes in patients with HGSC. Using EV-DNA whole-genome sequencing and EV-RNA sequencing, we identified distinct somatic EV-DNA alterations in cancer-hallmark genes and in ovarian cancer genes, as well as significantly altered oncogenic pathways between the R0 group and NACT groups. We also found significantly altered EV-RNA transcriptomic variations and enriched pathways between the groups. Taken together, our data suggest that the molecular characteristics of EVs could enable prediction of patients with HGSC who could undergo R0 surgery or respond to chemotherapy.
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- 2022
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12. Distinct T cell receptor repertoire diversity of clinically defined high-grade serous ovarian cancer treatment subgroups
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Sanghoon Lee, Li Zhao, Latasha D. Little, Shannon N. Westin, Amir A. Jazarei, Nicole D. Fleming, Jianhua Zhang, P. Andrew Futreal, and Anil K. Sood
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Biological Sciences ,Immunology ,Cancer ,Science - Abstract
Summary: In patients with high-grade serous ovarian cancer (HGSC), it is unclear which genomic features are related to complete gross resection (R0), which is typically associated with better clinical outcomes, or response to neoadjuvant chemotherapy (NACT). In this study, we evaluated T cell receptor (TCR) repertoire diversity in primary and metastatic tumor samples (n = 90) from clinically well-annotated patients with HGSC who achieved R0 or received NACT with excellent or poor response based on a laparoscopic triage algorithm. TCR sequencing followed by an integrative analysis with comprehensive multi-omics data identified higher TCR diversity (e.g., higher number of unique productive sequences and less clonal relatedness) in the R0 than NACT groups. We found enrichment of specific TCRβ genes usage, distinct mutual exclusiveness and co-occurrence pattern of TCRβ genes among the groups. We also found significantly positive correlations between clonal relatedness and neoantigens, copy number variations, and mutation load in the groups.
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- 2021
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13. A Modified 2 Tier Chemotherapy Response Score (CRS) and Other Histopathologic Features for Predicting Outcomes of Patients with Advanced Extrauterine High-Grade Serous Carcinoma after Neoadjuvant Chemotherapy
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Yanping Zhong, Jinsong Liu, Xiaoran Li, Shannon N. Westin, Anais Malpica, Barrett C. Lawson, Sanghoon Lee, Bryan M. Fellman, Robert L. Coleman, Anil K. Sood, and Nicole D. Fleming
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extrauterine ,high-grade serous carcinoma ,neoadjuvant chemotherapy ,chemotherapy response score ,pathology features ,survival ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background: The impact of chemotherapy response score (CRS) on prognosis has varied among studies. We addressed the prognostic significance of CRS and the prognostic value of previously undescribed histologic features using a cohort of 245 patients. Methods: Retrospective study in patients with advanced extrauterine high-grade serous carcinomas treated with neoadjuvant chemotherapy followed by interval tumor reductive surgery from 1990 to 2018 in our hospital. Gynecologic pathologists assessed tumor CRS and other histologic features. Clinical information was collected, and multivariate analyses were conducted. Results: A modified 2 tier CRS (CRS 1/2 versus CRS 3) was significantly associated, independent of scoring site (omental versus adnexal), with overall survival (OS) (omentum, p = 0.018; adnexa, p = 0.042; entire cohort, p = 0.002) and progression-free survival (PFS) (p = 0.021, p = 0.035, and p = 0.001, respectively). On multivariate survival analysis, 2 tier CRS, oncocytic change, inflammation, and desmoplasia were significant for OS (p = 0.034, p = 0.020, p = 0.007, and p = 0.010, respectively). Likewise, 2 tier CRS, inflammation, and desmoplasia were significant for PFS (p = 0.012, p = 0.003, p = 0.011, respectively). Conclusions: The modified 2 tier CRS was significantly associated with survival, independent of scoring site. Additional histologic features including oncocytic change, inflammation, and desmoplasia can also predict patient outcomes.
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- 2021
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14. Unusual indolent behavior of leiomyosarcoma of the vagina: Is observation a viable option?
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Ayatallah M. Khafagy, Lauren S. Prescott, Anais Malpica, and Shannon N. Westin
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Gynecology and obstetrics ,RG1-991 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2017
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15. Multicenter Phase II Trial of the WEE1 Inhibitor Adavosertib in Refractory Solid Tumors Harboring CCNE1 Amplification
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Siqing Fu, Shuyang Yao, Yuan Yuan, Rebecca A. Previs, Anthony D. Elias, Richard D. Carvajal, Thomas J. George, Ying Yuan, Lihou Yu, Shannon N. Westin, Yan Xing, Ecaterina E. Dumbrava, Daniel D. Karp, Sarina A. Piha-Paul, Apostolia M. Tsimberidou, Jordi Rodon Ahnert, Naoko Takebe, Karen Lu, Khandan Keyomarsi, and Funda Meric-Bernstam
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Cancer Research ,Oncology - Abstract
PURPOSE Preclinical cancer models harboring CCNE1 amplification were more sensitive to adavosertib treatment, a WEE1 kinase inhibitor, than models without amplification. Thus, we conducted this phase II study to assess the antitumor activity of adavosertib in patients with CCNE1-amplified, advanced refractory solid tumors. PATIENTS AND METHODS Patients aged ≥ 18 years with measurable disease and refractory solid tumors harboring CCNE1 amplification, an Eastern Cooperative Oncology Group performance status of 0-1, and adequate organ function were studied. Patients received 300 mg of adavosertib once daily on days 1 through 5 and 8 through 12 of a 21-day cycle. The trial followed Bayesian optimal phase II design. The primary end point was objective response rate (ORR). RESULTS Thirty patients were enrolled. The median follow-up duration was 9.9 months. Eight patients had partial responses (PRs), and three had stable disease (SD) ≥ 6 months, with an ORR of 27% (95% CI, 12 to 46), a SD ≥ 6 months/PR rate of 37% (95% CI, 20 to 56), a median progression-free survival duration of 4.1 months (95% CI, 1.8 to 6.4), and a median overall survival duration of 9.9 months (95% CI, 4.8 to 15). Fourteen patients with epithelial ovarian cancer showed an ORR of 36% (95% CI, 13 to 65) and SD ≥ 6 months/PR of 57% (95% CI, 29 to 82), a median progression-free survival duration of 6.3 months (95% CI, 2.4 to 10.2), and a median overall survival duration of 14.9 months (95% CI, 8.9 to 20.9). Common treatment-related toxicities were GI, hematologic toxicities, and fatigue. CONCLUSION Adavosertib monotherapy demonstrates a manageable toxicity profile and promising clinical activity in refractory solid tumors harboring CCNE1 amplification, especially in epithelial ovarian cancer. Further study of adavosertib, alone or in combination with other therapeutic agents, in CCNE1-amplified epithelial ovarian cancer is warranted.
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- 2023
16. Clinical implications of tumor‐based next‐generation sequencing in high‐grade epithelial ovarian cancer
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Katherine I. Foster, Kenna R. M. Shaw, Jeff Jin, Shannon N. Westin, Timothy A. Yap, Deanna M. Glassman, Amir A. Jazaeri, Jose A. Rauh‐Hain, Sanghoon Lee, Bryan M. Fellman, Zhenlin Ju, Yuexin Liu, Nicole D. Fleming, and Anil K. Sood
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Cancer Research ,Oncology - Published
- 2023
17. Targeting the DNA damage response beyond poly(ADP-ribose) polymerase inhibitors: novel agents and rational combinations
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Natalie Y.L. Ngoi, Shannon N. Westin, and Timothy A. Yap
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Cancer Research ,Oncology ,DNA Repair ,Neoplasms ,Humans ,Antineoplastic Agents ,Poly(ADP-ribose) Polymerase Inhibitors ,DNA Damage - Abstract
Poly(ADP-ribose) polymerase (PARP) inhibitors have transformed treatment paradigms in multiple cancer types defined by homologous recombination deficiency (HRD) and have become the archetypal example of synthetic lethal targeting within the DNA damage response (DDR). Despite this success, primary and acquired resistance to PARP inhibition inevitability threaten the efficacy and durability of response to these drugs. Beyond PARP inhibitors, recent advances in large-scale functional genomic screens have led to the identification of a steadily growing list of genetic dependencies across the DDR landscape. This has led to a wide array of novel synthetic lethal targets and corresponding inhibitors, which hold promise to widen the application of DDR inhibitors beyond HRD and potentially address PARP inhibitor resistance.In this review, we describe key synthetic lethal interactions that have been identified across the DDR landscape, summarize the early phase clinical development of the most promising DDR inhibitors, and highlight relevant combinations of DDR inhibitors with chemotherapy and other novel cancer therapies, which are anticipated to make an impact in rationally selected patient populations.The DDR landscape holds multiple opportunities for synthetic lethal targeting with multiple novel DDR inhibitors being evaluated on early phase clinical trials. Key challenges remain in optimizing the therapeutic window of ATR and WEE1 inhibitors as monotherapy and in combination approaches.
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- 2023
18. Adjuvant therapy in women with early stage uterine serous carcinoma: A multi-institutional study
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Katherine C. Kurnit, Silvana Pedra Nobre, Bryan M. Fellman, David A. Iglesias, Kristina Lindemann, Anuja Jhingran, Ane Gerda Z. Eriksson, Beyhan Ataseven, Gretchen E. Glaser, Jennifer J. Mueller, Shannon N. Westin, and Pamela T. Soliman
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Oncology ,Obstetrics and Gynecology - Abstract
Uterine serous carcinoma is a rare but aggressive subtype of endometrial adenocarcinoma. Our objective was to compare adjuvant treatment strategies for patients with early stage uterine serous carcinoma.This multi-institutional, retrospective cohort study evaluated patients with early stage uterine serous carcinoma. Patients with FIGO Stage IA-II disease after surgery, whose tumors had serous or any mixed serous/non-serous histology were included. Patients with carcinosarcoma were excluded. Clinical data were abstracted from local medical records. Summary statistics, Fisher's exact, and Kruskal-Wallis tests were used to analyze demographic and clinical characteristics. Univariable and multivariable analyses were performed for recurrence-free and overall survival.There were 737 patients included. Most patients had Stage IA disease (75%), 49% of which had no myometrial invasion. Only 164 (24%) tumors had lymphatic/vascular space invasion. Adjuvant treatment varied: 22% received no adjuvant therapy, 17% had chemotherapy alone, 19% had cuff brachytherapy, 35% had cuff brachytherapy with chemotherapy, and 6% underwent pelvic radiation. Adjuvant treatment was significantly associated with a decreased risk of recurrence (p = 0.04). Compared with no adjuvant therapy, patients who received brachytherapy or brachytherapy/chemotherapy had improved recurrence-free survival (HR 0.59, 95% CI 0.40-0.86; HR 0.65, 95% CI 0.49-0.88, respectively) and overall survival (HR 0.53, 95% CI 0.35-0.79; HR 0.49, 95% CI 0.35-0.69, respectively). Improved survival with brachytherapy and brachytherapy/chemotherapy persisted on multivariable analyses. Chemotherapy alone was also associated with improved overall survival compared with no adjuvant treatment (HR 0.55, 95% CI 0.37-0.81).Adjuvant therapy was associated with a decreased risk of recurrence relative to observation alone. Adjuvant cuff brachytherapy with and without chemotherapy was associated with improved survival outcomes in patients with early stage uterine serous carcinoma.
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- 2022
19. Contemporary primary treatment of women with stage II-IV low-grade serous ovarian/peritoneal cancer (LGSOC): Determinants of relapse and disease-free survival
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David M. Gershenson, Lauren P. Cobb, Shannon N. Westin, Yingao Zhang, Amir Jazaeri, Anais Malpica, and Charlotte C. Sun
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Oncology ,Obstetrics and Gynecology - Abstract
The purpose of the present study is to describe a cohort who received contemporary primary treatment for stage II-IV low-grade serous ovarian/peritoneal cancer (LGSOC), including patient characteristics and determinants of relapse and disease-free survival.The study included 99 patients: 1) with pathologically confirmed stage II-IV LGSOC of the ovary or peritoneum, 2) who underwent primary treatment consisting of cytoreductive surgery and either a) platinum/taxane chemotherapy followed by aromatase inhibitor maintenance therapy or b) aromatase inhibitor monotherapy, and 3) for whom there was availability of clinical data. Descriptive statistics were used to characterize clinicodemographic features. Subgroups were compared for PFS and OS. Multivariable Cox regression analyses were performed.Median PFS for the entire cohort was 56.8 months (95% CI, 41.3-NE), and median OS was 130.7 months (95% CI, 115.0-146.4). Forty-nine of 99 (49.5%) patients have relapsed to date. For these 49 patients, median time from diagnosis to relapse was 29.6 months (95% CI, 24.6-33.1) (range, 5.4-69.1 months). Only 1/49 (2%) patients who relapsed did so5 years from diagnosis. Fifty (50.0%) patients have not experienced disease progression or relapse. Median follow-up time for these 50 patients is 86.2 months (range, 25.3-169.0). Thirty-three of the 50 (66.0%) have been followed for5 years from diagnosis. On regression analyses, factors associated with improved patient outcomes-either PFS, OS, or both-included no gross residual disease, normal serum CA 125 at diagnosis, primary peritoneal site, and presence of extensive psammomatous calcifications.This is the first report to describe the clinicopathologic features and outcomes of women with stage II-IV LGSOC who received contemporary primary therapy.
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- 2022
20. Endometrial Cancer
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Shannon N. Westin, Karen H. Lu, and Jamal Rahaman
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- 2022
21. Targeting the ALK–CDK9-Tyr19 kinase cascade sensitizes ovarian and breast tumors to PARP inhibition via destabilization of the P-TEFb complex
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Yu-Yi Chu, Mei-Kuang Chen, Yongkun Wei, Heng-Huan Lee, Weiya Xia, Ying-Nai Wang, Clinton Yam, Jennifer L. Hsu, Hung-Ling Wang, Wei-Chao Chang, Hirohito Yamaguchi, Zhou Jiang, Chunxiao Liu, Ching-Fei Li, Lei Nie, Li-Chuan Chan, Yuan Gao, Shao-Chun Wang, Jinsong Liu, Shannon N. Westin, Sanghoon Lee, Anil K. Sood, Liuqing Yang, Gabriel N. Hortobagyi, Dihua Yu, and Mien-Chie Hung
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Cancer Research ,Ubiquitin-Protein Ligases ,Antineoplastic Agents ,Breast Neoplasms ,Poly(ADP-ribose) Polymerase Inhibitors ,Cyclin-Dependent Kinase 9 ,United States ,Mice ,Oncology ,Animals ,Humans ,Tyrosine ,Female ,Anaplastic Lymphoma Kinase ,Positive Transcriptional Elongation Factor B ,Poly(ADP-ribose) Polymerases ,Biomarkers - Abstract
Poly(ADP-ribose) polymerase (PARP) inhibitors have demonstrated promising clinical activity in multiple cancers. However, resistance to PARP inhibitors remains a substantial clinical challenge. In the present study, we report that anaplastic lymphoma kinase (ALK) directly phosphorylates CDK9 at tyrosine-19 to promote homologous recombination (HR) repair and PARP inhibitor resistance. Phospho-CDK9-Tyr19 increases its kinase activity and nuclear localization to stabilize positive transcriptional elongation factor b and activate polymerase II-dependent transcription of HR-repair genes. Conversely, ALK inhibition increases ubiquitination and degradation of CDK9 by Skp2, an E3 ligase. Notably, combination of US Food and Drug Administration-approved ALK and PARP inhibitors markedly reduce tumor growth and improve survival of mice in PARP inhibitor-/platinum-resistant tumor xenograft models. Using human tumor biospecimens, we further demonstrate that phosphorylated ALK (p-ALK) expression is associated with resistance to PARP inhibitors and positively correlated with p-Tyr19-CDK9 expression. Together, our findings support a biomarker-driven, combinatorial treatment strategy involving ALK and PARP inhibitors to induce synthetic lethality in PARP inhibitor-/platinum-resistant tumors with high p-ALK–p-Tyr19-CDK9 expression.
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- 2022
22. Intensity-Modulated Radiation Therapy Reduces Patient-Reported Chronic Toxicity Compared With Conventional Pelvic Radiation Therapy: Updated Results of a Phase III Trial
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Anamaria R. Yeung, Snehal Deshmukh, Ann H. Klopp, Karen M. Gil, Lari Wenzel, Shannon N. Westin, Andre A. Konski, David K. Gaffney, William Small, J. Spencer Thompson, Desiree E. Doncals, Guilherme H.C. Cantuaria, David P. D'Souza, Amy Chang, Vijayananda Kundapur, Dasarahally S. Mohan, Michael L. Haas, Yong Bae Kim, Catherine L. Ferguson, Stephanie L. Pugh, Lisa A. Kachnic, and Deborah W. Bruner
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Male ,Cancer Research ,Oncology ,Quality of Life ,Humans ,Female ,Patient Reported Outcome Measures ,Radiotherapy, Intensity-Modulated ,Radiotherapy, Conformal ,Antidiarrheals ,Radiation Injuries - Abstract
Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned coprimary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. The purpose of this update was to determine differences in patient-reported chronic toxicity and disease outcomes with intensity-modulated radiation therapy (IMRT) compared with conventional pelvic radiation. Patients with cervical and endometrial cancers who received postoperative pelvic radiation were randomly assigned to conventional radiation therapy (CRT) or IMRT. Toxicity and quality of life were assessed using Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events, Expanded Prostate Cancer Index Composite (EPIC) bowel and urinary domains, and Functional Assessment of Cancer Therapy–General. Between 2012 and 2015, 279 eligible patients were enrolled to the study with a median follow-up of 37.8 months. There were no differences in overall survival ( P = .53), disease-free survival ( P = .21), or locoregional failure ( P = .81). One year after RT, patients in the CRT arm experienced more high-level diarrhea frequency (5.8% IMRT v 15.1% CRT, P = .042) and a greater number had to take antidiarrheal medication two or more times a day (1.2% IMRT v 8.6% CRT, P = .036). At 3 years, women in the CRT arm reported a decline in urinary function, whereas the IMRT arm continued to improve (mean change in EPIC urinary score = 0.5, standard deviation = 13.0, IMRT v –6.0, standard deviation = 14.3, CRT, P = .005). In conclusion, IMRT reduces patient-reported chronic GI and urinary toxicity with no difference in treatment efficacy at 3 years.
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- 2022
23. Stranger Things: New Roles and Opportunities for Androgen Receptor in Oncology Beyond Prostate Cancer
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Javier Leo, Eleonora Dondossola, Kaitlin J Basham, Nathaniel R Wilson, Omar Alhalabi, Jianjun Gao, Katherine C Kurnit, Michael G White, Jennifer L McQuade, Shannon N Westin, Elizabeth A Wellberg, and Daniel E Frigo
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Endocrinology - Abstract
The androgen receptor (AR) is one of the oldest therapeutic targets in oncology and continues to dominate the treatment landscape for advanced prostate cancer, where nearly all treatment regimens include some form of AR modulation. In this regard, AR remains the central driver of prostate cancer cell biology. Emerging preclinical and clinical data implicate key roles for AR in additional cancer types, thereby expanding the importance of this drug target beyond prostate cancer. In this mini-review, new roles for AR in other cancer types are discussed as well as their potential for treatment with AR-targeted agents. Our understanding of these additional functions for AR in oncology expand this receptor’s potential as a therapeutic target and will help guide the development of new treatment approaches.
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- 2023
24. State of the science: Contemporary front-line treatment of advanced ovarian cancer
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Emily, Hinchcliff, Shannon N, Westin, and Thomas J, Herzog
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Ovarian Neoplasms ,Oncology ,Humans ,Obstetrics and Gynecology ,Female ,Carcinoma, Ovarian Epithelial - Published
- 2022
25. Frailty repels the knife: The impact of frailty index on surgical intervention and outcomes
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Katelyn F, Handley, Anil K, Sood, Graziela Zibetti Dal, Molin, Shannon N, Westin, Larissa A, Meyer, Bryan, Fellman, Pamela T, Soliman, Robert L, Coleman, and Nicole D, Fleming
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Ovarian Neoplasms ,Postoperative Complications ,Treatment Outcome ,Frailty ,Oncology ,Humans ,Obstetrics and Gynecology ,Female ,Laparoscopy ,Severity of Illness Index ,Neoplasm Staging ,Retrospective Studies - Abstract
To assess the impact of frailty in patients with ovarian cancer on surgical procedures and outcomes.A retrospective review of patients with stage II-IV ovarian cancer from April 2013 to September 2017 was performed. Patients were triaged by laparoscopy to determine primary resectability. The adjusted modified frailty index score (amFI) was calculated and amFI ≥2 classified as high frailty. Clinical outcomes, progression free survival (PFS) and overall survival (OS) were estimated.592 patients met inclusion criteria; amFI of 0, 1 and ≥ 2 was noted in 57%, 29%, and 14%, respectively. Patients with high frailty were less likely to be offered laparoscopic assessment for primary surgery (49% v. 43% v. 28% for amFI = 0, 1, and ≥ 2, p = 0.004), and more likely to have a Fagotti score ≥ 8 (58%, 48%, and 34%, p = 0.04). Only 17% of the high frailty cohort had primary tumor reductive surgery compared to 26% and 34% in patients with amFI = 1 and amFI = 0 (p = 0.02). Furthermore, patients with higher amFI were less likely to undergo any tumor reductive surgery (85% v. 74% v. 59%, p0.001). Postoperative complications were more frequent in patients with higher amFI (44% v. 56% v. 64%, p = 0.01). Death within thirty days of treatment initiation was significantly higher in patients with high frailty (0.4% v. 2% v. 9%, p = 0.005). In multivariate analysis, high frailty was associated with worse PFS (p = 0.02) and OS (p0.05).Postoperative morbidity, PFS, and OS were worse in patients with high frailty scores. Quantification of frailty may be useful for clinical decision making in patients with newly diagnosed advanced ovarian cancer.
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- 2022
26. Phase II Trial of MEDI0457 and Durvalumab for Patients With Recurrent/Metastatic Human Papillomavirus-Associated Cancers
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Van K Morris, Amir Jazaeri, Shannon N Westin, Curtis Pettaway, Solly George, Ryan W Huey, Michaela Grinsfelder, Aaron Shafer, Benny Johnson, David Vining, Ming Guo, Bryan Fellman, and Michael Frumovitz
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Cancer Research ,Oncology - Abstract
Background Human papillomavirus (HPV) types 16/18 drive oncogenesis for most patients with cervical, anal, and penile cancers. MEDI0457, a therapeutic DNA vaccine containing plasmids for E6 and E7 HPV-16/18 viral oncogenes and IL-12 adjuvant, is safe and provokes an immune response against E6/E7. We tested MEDI0457 with the anti-PD-L1 antibody durvalumab for patients with HPV-associated cancers. Methods Patients with recurrent/metastatic, treatment-refractory HPV-16/18 cervical cancer, or rare HPV-associated (anal and penile) cancers were eligible. Prior immune checkpoint inhibition was not permitted. Patients received MEDI0457 7 mg intramuscularly (weeks 1, 3, 7, 12, and every 8 weeks thereafter) and durvalumab 1500 mg intravenously every 4 weeks. The primary endpoint was overall response (RECIST 1.1). In this Simon two-stage phase 2 trial (Ho: p Results Twenty-one patients (12 cervical, 7 anal, and 2 penile) were evaluable for toxicity and 19 for response Overall response rate was 21% (95% CI, 6%-46%) among evaluable patients. Disease control rate was 37% (95% CI, 16%-62%). Median duration of response among responders was 21.8 months (95% CI, 9.7%-not estimable). Median progression-free survival was 4.6 months (95% CI, 2.8%-7.2%). Median overall survival was 17.7 months (95% CI, 7.6%-not estimable). Grades 3-4 treatment-related adverse events occurred in 6 (23%) participants. Conclusions The combination of MEDI0457 and durvalumab demonstrated acceptable safety and tolerability in patients with advanced HPV-16/18 cancers. The low ORR among patients with cervical cancer led to study discontinuation despite a clinically meaningful disease control rate.
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- 2023
27. Data from Rational Combination of CRM1 Inhibitor Selinexor and Olaparib Shows Synergy in Ovarian Cancer Cell Lines and Mouse Models
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Anil K. Sood, Prahlad T. Ram, Shannon N. Westin, Yosef Landesman, Robert L. Coleman, Clifford Stephan, Paola Amero, Yunfei Wen, Deanna Glassman, Sujanitha Umamaheswaran, Mark Kim, Cristina Ivan, Mary Sobieski, Reid T. Powell, Nghi Nguyen, Santosh K. Dasari, Emine Bayraktar, Robiya Joseph, Elaine Stur, Shaolin Ma, Cristian Rodriguez-Aguayo, and Katelyn F. Handley
- Abstract
CRM1 inhibitors have demonstrated antitumor effects in ovarian and other cancers; however, rational combinations are largely unexplored. We performed a high-throughput drug library screen to identify drugs that might combine well with selinexor in ovarian cancer. Next, we tested the combination of selinexor with the top hit from the drug screen in vitro and in vivo. Finally, we assessed for mechanisms underlying the identified synergy using reverse phase protein arrays (RPPA). The drug library screen assessing 688 drugs identified olaparib (a PARP inhibitor) as the most synergistic combination with selinexor. Synergy was further demonstrated by MTT assays. In the A2780luc ip1 mouse model, the combination of selinexor and olaparib yielded significantly lower tumor weight and fewer tumor nodules compared with the control group (P < 0.04 and P < 0.03). In the OVCAR5 mouse model, the combination yielded significantly fewer nodules (P = 0.006) and markedly lower tumor weight compared with the control group (P = 0.059). RPPA analysis indicated decreased expression of DNA damage repair proteins and increased expression of tumor suppressor proteins in the combination treatment group. Collectively, our preclinical findings indicate that combination with selinexor to expand the utility and efficacy of PARP inhibitors in ovarian cancer warrants further exploration.
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- 2023
28. Supplementary Data from Rational Combination of CRM1 Inhibitor Selinexor and Olaparib Shows Synergy in Ovarian Cancer Cell Lines and Mouse Models
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Anil K. Sood, Prahlad T. Ram, Shannon N. Westin, Yosef Landesman, Robert L. Coleman, Clifford Stephan, Paola Amero, Yunfei Wen, Deanna Glassman, Sujanitha Umamaheswaran, Mark Kim, Cristina Ivan, Mary Sobieski, Reid T. Powell, Nghi Nguyen, Santosh K. Dasari, Emine Bayraktar, Robiya Joseph, Elaine Stur, Shaolin Ma, Cristian Rodriguez-Aguayo, and Katelyn F. Handley
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Revised Supplementary Data Demonstrating All Supplementary Figures 1-6 and Supplementary Table 1
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- 2023
29. Supplementary Tables from Phase Ib Dose Expansion and Translational Analyses of Olaparib in Combination with Capivasertib in Recurrent Endometrial, Triple-Negative Breast, and Ovarian Cancer
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Gordon B. Mills, Robert L. Coleman, Anil K. Sood, Charlotte C. Sun, Larissa A. Meyer, Rashmi Murthy, Karen H. Lu, Amir Jazaeri, Katheleen M. Schmeler, Michael Frumovitz, Pamela T. Soliman, Nashwa Kabil, Tsun Hsuan Chen, Anca Chelariu-Raicu, Jinsong Liu, Tae-Beom Kim, Sanghoon Lee, Ying Yuan, Bryan Fellman, Allison Creason, XiaoYan Ma, Ningping Feng, Joseph R. Marszalek, Christopher P. Vellano, Yong Fang, Aurora Blucher, Jennifer K. Litton, Marilyne Labrie, and Shannon N. Westin
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Supplementary Tables
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- 2023
30. Figure_S2 from Phase Ib Dose Expansion and Translational Analyses of Olaparib in Combination with Capivasertib in Recurrent Endometrial, Triple-Negative Breast, and Ovarian Cancer
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Gordon B. Mills, Robert L. Coleman, Anil K. Sood, Charlotte C. Sun, Larissa A. Meyer, Rashmi Murthy, Karen H. Lu, Amir Jazaeri, Katheleen M. Schmeler, Michael Frumovitz, Pamela T. Soliman, Nashwa Kabil, Tsun Hsuan Chen, Anca Chelariu-Raicu, Jinsong Liu, Tae-Beom Kim, Sanghoon Lee, Ying Yuan, Bryan Fellman, Allison Creason, XiaoYan Ma, Ningping Feng, Joseph R. Marszalek, Christopher P. Vellano, Yong Fang, Aurora Blucher, Jennifer K. Litton, Marilyne Labrie, and Shannon N. Westin
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Supplementary Figure S2
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- 2023
31. Supplemental Figures 1-5, Tables 4-6 from Integrative Protein-Based Prognostic Model for Early-Stage Endometrioid Endometrial Cancer
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Han Liang, Gordon B. Mills, Helga B. Salvesen, Jone Trovik, Mari K. Halle, Yiling Lu, Shannon N. Westin, Jie Li, Henrica M.J. Werner, and Ji-Yeon Yang
- Abstract
Supplemental Figures 1-5, Tables 4-6. Supplemental Figure 1. Kaplan-Meier curves comparing overall survivals for the training and validation cohorts Supplemental Figure 2. Kaplan-Meier curves for the late-stage EEC samples (FIGO 2009 stages III & IV) in the training and validation cohorts. Supplemental Figure 3. Plots in the first column display the distributions of risk scores of earlystage EEC samples in the training and validation cohorts. Supplemental Figure 4. Kaplan-Meier curves for the early-stage and late-stage EEC samples in the training and validation cohorts. Supplemental Figure 5. Kaplan-Meier curves for the late-stage EEC samples (stages III & IV) in the training and validation cohorts. Risk scores for patients were computed using the late-stage integrative model. Supplemental Table 4. Markers comprising the integrative model for the patients with early-stage EEC Supplemental Table 5. Markers included the integrative model for patients with late-stage EEC Supplemental Table 6. Univariate and multivariate Cox's proportional hazards model analysis for the late-stage EEC samples
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- 2023
32. Supplementary Data from Phase Ib Dose Expansion and Translational Analyses of Olaparib in Combination with Capivasertib in Recurrent Endometrial, Triple-Negative Breast, and Ovarian Cancer
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Gordon B. Mills, Robert L. Coleman, Anil K. Sood, Charlotte C. Sun, Larissa A. Meyer, Rashmi Murthy, Karen H. Lu, Amir Jazaeri, Katheleen M. Schmeler, Michael Frumovitz, Pamela T. Soliman, Nashwa Kabil, Tsun Hsuan Chen, Anca Chelariu-Raicu, Jinsong Liu, Tae-Beom Kim, Sanghoon Lee, Ying Yuan, Bryan Fellman, Allison Creason, XiaoYan Ma, Ningping Feng, Joseph R. Marszalek, Christopher P. Vellano, Yong Fang, Aurora Blucher, Jennifer K. Litton, Marilyne Labrie, and Shannon N. Westin
- Abstract
Supplementary Figures Legends
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- 2023
33. Supplementary Figure 1 from Everolimus, Letrozole, and Metformin in Women with Advanced or Recurrent Endometrioid Endometrial Cancer: A Multi-Center, Single Arm, Phase II Study
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Robert L. Coleman, Karen H. Lu, Brian M. Slomovitz, Russell R. Broaddus, Melinda S. Yates, Qian Zhang, Ying Yuan, Bryan M. Fellman, David A. Iglesias, Shannon N. Westin, and Pamela T. Soliman
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Supplementary Figure S1
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- 2023
34. Data from Phase Ib Dose Expansion and Translational Analyses of Olaparib in Combination with Capivasertib in Recurrent Endometrial, Triple-Negative Breast, and Ovarian Cancer
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Gordon B. Mills, Robert L. Coleman, Anil K. Sood, Charlotte C. Sun, Larissa A. Meyer, Rashmi Murthy, Karen H. Lu, Amir Jazaeri, Katheleen M. Schmeler, Michael Frumovitz, Pamela T. Soliman, Nashwa Kabil, Tsun Hsuan Chen, Anca Chelariu-Raicu, Jinsong Liu, Tae-Beom Kim, Sanghoon Lee, Ying Yuan, Bryan Fellman, Allison Creason, XiaoYan Ma, Ningping Feng, Joseph R. Marszalek, Christopher P. Vellano, Yong Fang, Aurora Blucher, Jennifer K. Litton, Marilyne Labrie, and Shannon N. Westin
- Abstract
Purpose:On the basis of strong preclinical rationale, we sought to confirm recommended phase II dose (RP2D) for olaparib, a PARP inhibitor, combined with the AKT inhibitor capivasertib and assess molecular markers of response and resistance.Patients and Methods:We performed a safety lead-in followed by expansion in endometrial, triple-negative breast, ovarian, fallopian tube, or peritoneal cancer. Olaparib 300 mg orally twice daily and capivasertib orally twice daily on a 4-day on 3-day off schedule was evaluated. Two dose levels (DL) of capivasertib were planned: 400 mg (DL1) and 320 mg (DL-1). Patients underwent biopsies at baseline and 28 days.Results:A total of 38 patients were enrolled. Seven (18%) had germline BRCA1/2 mutations. The first 2 patients on DL1 experienced dose-limiting toxicities (DLT) of diarrhea and vomiting. No DLTs were observed on DL-1 (n = 6); therefore, DL1 was reexplored (n = 6) with no DLTs, confirming DL1 as RP2D. Most common treatment-related grade 3/4 adverse events were anemia (23.7%) and leukopenia (10.5%). Of 32 evaluable subjects, 6 (19%) had partial response (PR); PR rate was 44.4% in endometrial cancer. Seven (22%) additional patients had stable disease greater than 4 months. Tumor analysis demonstrated strong correlations between response and immune activity, cell-cycle alterations, and DNA damage response. Therapy resistance was associated with receptor tyrosine kinase and RAS-MAPK pathway activity, metabolism, and epigenetics.Conclusions:The combination of olaparib and capivasertib is associated to no serious adverse events and demonstrates durable activity in ovarian, endometrial, and breast cancers, with promising responses in endometrial cancer. Importantly, tumor samples acquired pre- and on-therapy can help predict patient benefit.
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- 2023
35. Supplementary materials from Phase Ib Dose Expansion and Translational Analyses of Olaparib in Combination with Capivasertib in Recurrent Endometrial, Triple-Negative Breast, and Ovarian Cancer
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Gordon B. Mills, Robert L. Coleman, Anil K. Sood, Charlotte C. Sun, Larissa A. Meyer, Rashmi Murthy, Karen H. Lu, Amir Jazaeri, Katheleen M. Schmeler, Michael Frumovitz, Pamela T. Soliman, Nashwa Kabil, Tsun Hsuan Chen, Anca Chelariu-Raicu, Jinsong Liu, Tae-Beom Kim, Sanghoon Lee, Ying Yuan, Bryan Fellman, Allison Creason, XiaoYan Ma, Ningping Feng, Joseph R. Marszalek, Christopher P. Vellano, Yong Fang, Aurora Blucher, Jennifer K. Litton, Marilyne Labrie, and Shannon N. Westin
- Abstract
Supplementary materials
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- 2023
36. Data from Everolimus, Letrozole, and Metformin in Women with Advanced or Recurrent Endometrioid Endometrial Cancer: A Multi-Center, Single Arm, Phase II Study
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Robert L. Coleman, Karen H. Lu, Brian M. Slomovitz, Russell R. Broaddus, Melinda S. Yates, Qian Zhang, Ying Yuan, Bryan M. Fellman, David A. Iglesias, Shannon N. Westin, and Pamela T. Soliman
- Abstract
Purpose:Treatment for patients with recurrent endometrioid endometrial cancer (EEC) are limited as paclitaxel is the only second-line chemotherapy with a response rate >13%. Targeting PIK3/mTOR in combination with hormonal therapy has shown promise. The addition of metformin may enhance this response. We conducted a phase II study evaluating everolimus, letrozole, and metformin in advanced/recurrent EEC.Patients and Methods:A Simon two-stage design was employed. Women with ≤2 prior chemotherapy regimens for recurrence were eligible. Pretreatment biopsy was required, followed by everolimus 10 mg orally, letrozole 2.5 mg orally, and metformin 500 mg orally twice a day on a 4-week cycle. The primary endpoint was clinical benefit (CB), defined as complete response (CR), partial response (PR), or stable disease (SD) confirmed at 16 weeks. Patients were treated until progression or toxicity.Results:Sixty-two patients were enrolled. Median age was 62 years (40–77) with 401 cycles completed, median of 6 cycles (1–31). Fifty-four patients were evaluable for response with a CB rate of 50% (27/54). Best overall response (OR) was PR 28% (15/54) and SD 22% (12/54). Thirteen patients received >12 cycles. Median follow-up was 17.9 months (2–47). Median progression-free survival was 5.7 [95% confidence interval (CI), 3.0–8.1] and OS was 19.6 months (95% CI, 14.2–26.3). Positive progesterone receptor expression was associated with CB (89.5% vs. 27.3%, P = 0.001).Conclusions:Everolimus, letrozole, and metformin resulted in 50% CB and 28% OR in women with recurrent EEC. Progesterone receptor–positive tumors may have better response; validation studies are needed.See related commentary by Madariaga et al., p. 523
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- 2023
37. Supplementary Figure 2 from Everolimus, Letrozole, and Metformin in Women with Advanced or Recurrent Endometrioid Endometrial Cancer: A Multi-Center, Single Arm, Phase II Study
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Robert L. Coleman, Karen H. Lu, Brian M. Slomovitz, Russell R. Broaddus, Melinda S. Yates, Qian Zhang, Ying Yuan, Bryan M. Fellman, David A. Iglesias, Shannon N. Westin, and Pamela T. Soliman
- Abstract
Supplementary Figure S2
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- 2023
38. Supplemental Table 2 from Integrative Protein-Based Prognostic Model for Early-Stage Endometrioid Endometrial Cancer
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Han Liang, Gordon B. Mills, Helga B. Salvesen, Jone Trovik, Mari K. Halle, Yiling Lu, Shannon N. Westin, Jie Li, Henrica M.J. Werner, and Ji-Yeon Yang
- Abstract
Supplemental Table 2. Clinical information and RPPA data on patients in the validation set
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- 2023
39. Data from Integrative Protein-Based Prognostic Model for Early-Stage Endometrioid Endometrial Cancer
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Han Liang, Gordon B. Mills, Helga B. Salvesen, Jone Trovik, Mari K. Halle, Yiling Lu, Shannon N. Westin, Jie Li, Henrica M.J. Werner, and Ji-Yeon Yang
- Abstract
Purpose: Endometrioid endometrial carcinoma (EEC) is the major histologic type of endometrial cancer, the most prevalent gynecologic malignancy in the United States. EEC recurrence or metastasis is associated with a poor prognosis. Early-stage EEC is generally curable, but a subset has high risk of recurrence or metastasis. Prognosis estimation for early-stage EEC mainly relies on clinicopathologic characteristics, but is unreliable. We aimed to identify patients with high-risk early-stage EEC who are most likely to benefit from more extensive surgery and adjuvant therapy by building a prognostic model that integrates clinical variables and protein markers.Experimental Design: We used two large, independent early-stage EEC datasets as training (n = 183) and validation cohorts (n = 333), and generated the levels of 186 proteins and phosphoproteins using reverse-phase protein arrays. By applying an initial filtering and the elastic net to the training samples, we developed a prognostic model for overall survival containing two clinical variables and 18 protein markers and optimized the risk group classification.Results: The Kaplan–Meier survival analyses in the validation cohort confirmed an improved discriminating power of our prognostic model for patients with early-stage EEC over key clinical variables (log-rank test, P = 0.565 for disease stage, 0.567 for tumor grade, and 1.3 × 10−4 for the integrative model). Compared with clinical variables (stage, grade, and patient age), only the risk groups defined by the integrative model were consistently significant in both univariate and multivariate analyses across both cohorts.Conclusions: Our prognostic model is potentially of high clinical value for stratifying patients with early-stage EEC and improving their treatment strategies. Clin Cancer Res; 22(2); 513–23. ©2015 AACR.
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- 2023
40. Supplementary material from A Phase I Open-Label Study to Identify a Dosing Regimen of the Pan-AKT Inhibitor AZD5363 for Evaluation in Solid Tumors and in PIK3CA-Mutated Breast and Gynecologic Cancers
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Jan H.M. Schellens, James Yates, Gaia Schiavon, Paul Rugman, Vicky Rowlands, Martin Pass, Rhiannon Maudsley, Justin P.O. Lindemann, Peter Lawrence, Andrew Foxley, Paul Elvin, Elza C. de Bruin, Barry R. Davies, Marie Cullberg, Claire Corcoran, S.Y. Amy Cheung, T. Hedley Carr, J. Carl Barrett, Helen Ambrose, Mathew Tall, Michelle D. Garrett, Peter Kabos, Shannon N. Westin, Benoit You, Philippe L. Bedard, Gerald Batist, J. Alejandro Pérez-Fidalgo, Emma J. Dean, and Udai Banerji
- Abstract
Supplementary methods and results Supplementary Figure 1. Study 1 (NCT01226316) design Supplementary Figure 2. Dose escalation and DLTs in Part A, with MTDs of the continuous, 4/7, and 2/7 schedules being 320, 480, and 640 mg bid, respectively Supplementary Figure 3. Exploratory mutation analyses (ddPCR) in archival tissue and plasma (ctDNA) samples from a breast cancer patient who had progressive disease as best response (Cb cohort) Supplementary Figure 4. A) Tumour growth inhibition in preclinical tumor xenograft models (BT474c, HGC-27, HCC1954 and 786.0) treated with AZD5363 bid po at the indicated doses. B) AZD5363 PD in BT474c tumor xenografts. C) AZD5363 PD at steady state in BT474c xenograft tumors. D) Time course of pPRAS40 and pAkt S473 in BT474c tumor xenograft tissue following the final dose of AZD5363 after 3 weeks' continuous (100 mg/kg bid) or intermittent dosing (130 mg/kg bid 4/7 and 170 mg/kg bid 2/7) Supplementary Figure 5. Glucose (non-fasting/random) values over time after 480 mg single-dose AZD5363 (all dosing schedules) Supplementary Table 1. Percentage change from baseline for PoM biomarkers for 12 evaluable patients Supplementary Table 2. Antibodies and conditions for IHC analysis Supplementary Table 3. ddPCR primers and probes Supplementary Table 4. Tables with results of molecular analyses of Part C patients (PIK3CA and ESR1 mutation status in tissue and ctDNA, PTEN status in archival tissue) Supplementary Table 5. AEs of CTCAE grade {greater than or equal to}3 (irrespective of causality) in Parts A and B (frequency >3% total) and Part C (frequency >5% total)
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- 2023
41. Data from A Phase I Open-Label Study to Identify a Dosing Regimen of the Pan-AKT Inhibitor AZD5363 for Evaluation in Solid Tumors and in PIK3CA-Mutated Breast and Gynecologic Cancers
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Jan H.M. Schellens, James Yates, Gaia Schiavon, Paul Rugman, Vicky Rowlands, Martin Pass, Rhiannon Maudsley, Justin P.O. Lindemann, Peter Lawrence, Andrew Foxley, Paul Elvin, Elza C. de Bruin, Barry R. Davies, Marie Cullberg, Claire Corcoran, S.Y. Amy Cheung, T. Hedley Carr, J. Carl Barrett, Helen Ambrose, Mathew Tall, Michelle D. Garrett, Peter Kabos, Shannon N. Westin, Benoit You, Philippe L. Bedard, Gerald Batist, J. Alejandro Pérez-Fidalgo, Emma J. Dean, and Udai Banerji
- Abstract
Purpose: This phase I, open-label study (Study 1, D3610C00001; NCT01226316) was the first-in-human evaluation of oral AZD5363, a selective pan-AKT inhibitor, in patients with advanced solid malignancies. The objectives were to investigate the safety, tolerability, and pharmacokinetics of AZD5363, define a recommended dosing schedule, and evaluate preliminary clinical activity.Experimental Design: Patients were aged ≥18 years with World Health Organization (WHO) performance status of 0 to 1. Dose escalation was conducted within separate continuous and intermittent [4 days/week (4/7) or 2 days/week (2/7)] schedules with safety, pharmacokinetic, and pharmacodynamic analyses. Expansion cohorts of approximately 20 patients each explored AZD5363 activity in PIK3CA-mutant breast and gynecologic cancers.Results: MTDs were 320, 480, and 640 mg for continuous (n = 47), 4/7 (n = 21), and 2/7 (n = 22) schedules, respectively. Dose-limiting toxicities were rash and diarrhea for continuous, hyperglycemia for 2/7, and none for 4/7. Common adverse events were diarrhea (78%) and nausea (49%) and, for Common Terminology Criteria for Adverse Events grade ≥3 events, hyperglycemia (20%). The recommended phase II dose (480 mg bid, 4/7 intermittent) was assessed in PIK3CA-mutant breast and gynecologic expansion cohorts: 46% and 56% of patients, respectively, showed a reduction in tumor size, with RECIST responses of 4% and 8%. These responses were less than the prespecified 20% response rate; therefore, the criteria to stop further recruitment to the PIK3CA-mutant cohort were met.Conclusions: At the recommended phase II dose, AZD5363 was well tolerated and achieved plasma levels and robust target modulation in tumors. Proof-of-concept responses were observed in patients with PIK3CA-mutant cancers treated with AZD5363. Clin Cancer Res; 24(9); 2050–9. ©2017 AACR.See related commentary by Costa and Bosch, p. 2029
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- 2023
42. Outcomes of patients with therapy‐related myeloid neoplasms after treatment with poly( <scp>ADP</scp> ‐ribose) polymerase proteins inhibitors for solid tumours
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Emmanuel Almanza‐Huante, Alex Bataller, Samuel Urrutia, Georgina Gener‐Ricos, Robert Edward Briski, Rashmi Kanagal‐Shamanna, Karen H. Lu, Shannon N. Westin, Timothy A. Yap, Koichi Takahashi, Farhad Ravandi, Yesid Alvarado, Tapan Kadia, Koiji Sasaki, Hagop M. Kantarjian, and Guillermo Garcia‐Manero
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Hematology - Published
- 2023
43. Clinical outcomes of leuprolide acetate in the treatment of recurrent ovarian granulosa cell tumors
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Katherine I. Foster, Alejandra Flores Legarreta, Rhea Kamat, Katelyn F. Handley, Deanna Glassman, Jeffrey A. How, Barrett C. Lawson, Shannon N. Westin, Lois M. Ramondetta, Michael Frumovitz, David M. Gershenson, Anil K. Sood, and R. Tyler Hillman
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Obstetrics and Gynecology - Published
- 2023
44. Clinical analysis of pathologic complete responders in advanced-stage ovarian cancer
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Christopher J. LaFargue, Katelyn F. Handley, Nicole D. Fleming, Alpa M. Nick, Anca Chelariu-Raicu, Bryan Fellman, Tara Castellano, Aiko Ogasawara, Marianne Hom-Tedla, Erin A. Blake, Alexandre A.B.A. da Costa, Aleia K. Crim, Alejandro Rauh-Hain, Shannon N. Westin, Robert L. Coleman, Koji Matsuo, Glauco Baiocchi, Kosei Hasegawa, Kathleen Moore, and Anil K. Sood
- Subjects
Ovarian Neoplasms ,Neoplasm, Residual ,Oncology ,Chemotherapy, Adjuvant ,Humans ,Obstetrics and Gynecology ,Female ,Carcinoma, Ovarian Epithelial ,Article ,Neoadjuvant Therapy ,Neoplasm Staging ,Retrospective Studies - Abstract
OBJECTIVE: To determine the clinical characteristics of patients who attained pathologic complete response (pCR) after neoadjuvant chemotherapy (NACT) and to identify specific predictive or prognostic factors associated with pCR. METHODS: Two distinct populations of patients who underwent NACT followed by interval tumor reductive surgery (TRS) were used in this retrospective study. The first contained 472 patients from a single institution. The second contained only pCR patients (67); those identified from population one, plus 44 obtained through collaborative institutions. Cox analysis and log-rank tests were performed to assess associations between clinical characteristics and pCR outcome, recurrence-free survival (RFS), and overall survival (OS). RESULTS: The median RFS and OS in our pCR-only population was 24.2 and 80.8 months, respectively, with a median follow-up time of 32.4 months. In our single institution population, 23 patients attained pCR (4.9%) and had longer RFS compared to non-pCR patients with viable microscopic, optimal, or suboptimal residual disease (24.3 vs. 12.1 vs. 11.6 vs. 9.6 months, p = 0.025, 0.012, 0.008, respectively), and longer OS compared to those with optimal or suboptimal residual disease (54.5 vs. 29.4 vs. 25.7 months, p = 0.027, 0.007, respectively). Patients were more than three-fold likely to attain pCR if their CA125 value was normal at the time of surgery (OR 3.54, 95% CI:1.14 – 11.05, p = 0.029). CONCLUSIONS: Women with pCR after NACT have significantly longer RFS compared to those with residual viable tumor at the time of interval tumor-reductive surgery, and CA125 is plausible biomarker for identifying these extreme responders preoperatively.
- Published
- 2022
45. Targeting CCR2+ macrophages with BET inhibitor overcomes adaptive resistance to anti-VEGF therapy in ovarian cancer
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Yutuan Wu, Nicholas B. Jennings, Yunjie Sun, Santosh K. Dasari, Emine Bayraktar, Sara Corvigno, Elaine Stur, Deanna Glassman, Lingegowda S. Mangala, Adrian Lankenau Ahumada, Shannon N. Westin, Anil K. Sood, and Wei Hu
- Subjects
Cancer Research ,Oncology ,General Medicine - Abstract
Purpose Tumor-associated macrophages (TAMs) are known to contribute to adaptive resistance to anti-vascular endothelial growth factor (VEGF) antibody (AVA) therapy in ovarian cancer. BET (bromodomain and extra-terminal domain) inhibitors (BETi) may have unique roles in targeting TAMs. Our objective was to examine the effects of BETi on TAMs, especially in the context of enhancing the efficacy of AVA therapy. Methods We conducted a series of in vitro (MTT assay, apoptosis, flow cytometry, and RNA sequencing) and in vivo (xenograft ovarian cancer model) experiments to determine the biological effects of BETi combined with AVA in ovarian cancer. For statistical analysis, a two-tailed Student’s t test (equal variance) or ANOVA was used for multiple groups’ comparison, and p Results BETi resulted in a dose-dependent decrease in cell viability and induced apoptosis (p p p +/CD80+) was significantly increased after treatment with low-dose BETi (ABBV-075 0.1 µM; p +/CCR2+ macrophages was significantly decreased (p + macrophages and re-polarize the macrophages into an M1-like phenotype. RNA-seq analysis revealed that BETi selectively targeted macrophage infiltration-related cytokines/chemokines in ovarian cancer (adjusted p p p Conclusions Our findings indicate a previously unrecognized role for BETi in selectively targeting CCR2+ TAMs and enhancing the efficacy of AVA therapy in ovarian cancer.
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- 2022
46. Contributors
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Floor J. Backes, Lindsey B. Beffa, Caroline C. Billingsley, Michael J. Birrer, Kristin Bixel, Teresa K.L. Boitano, Wendy R. Brewster, Dana M. Chase, Shaina Bruce, Angelena Crown, Christina S. Chu, Daniel L. Clarke-Pearson, Robert A. Ross, Brian Crosland, Joshua G. Cohen, Robert L. Coleman, Paul A. DiSilvestro, Oliver Dorigo, Linda R. Duska, Ramez Nassef Eskander, Mary L. Gemignani, Camille Catherine Gunderson, Andrea R. Hagemann, Thomas J. Herzog, Travis R. Korenaga, Warner K. Huh, Lindsay Kuroki, Katherine Kurnit, Robert S. Mannel, L. Stewart Massad, Cara A. Mathews, David S. Miller, Bradley J. Monk, David G. Mutch, Rachita Nikam, JoAnn V. Pinkerton, Matthew Powell, Dominique L. Rash, Lisa M. Landrum, Kari L. Ring, Malte Renz, Brandon Roane, Stephen C. Rubin, Ritu Salani, Jane Satero, Anil K. Sood, John T. Soper, Elizabeth Christina Stock, C. James Sung, Krishnansu Sujata Tewari, Michael D. Toboni, Katherine Tucker, Joan L. Walker, Jaclyn A. Wall, Christina Washington, Lari B. Wenzel, Shannon N. Westin, Catheryn M. Yashar, William T. Creasman, and Rosemary E. Zuna
- Published
- 2023
47. Epithelial ovarian cancer
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Katherine Kurnit, Shannon N. Westin, and Ritu Salani
- Published
- 2023
48. Rational Combination of CRM1 Inhibitor Selinexor and Olaparib Shows Synergy in Ovarian Cancer Cell Lines and Mouse Models
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Robert L. Coleman, Emine Bayraktar, Paola Amero, Cristina Ivan, Katelyn F. Handley, Cristian Rodriguez-Aguayo, Prahlad T. Ram, Deanna Glassman, Clifford Stephan, Anil K. Sood, Mark Seungwook Kim, Mary Sobieski, Elaine Stur, Nghi Nguyen, Shaolin Ma, Sujanitha Umamaheswaran, Yunfei Wen, Santosh K. Dasari, Reid T. Powell, Robiya Joseph, Yosef Landesman, and Shannon N. Westin
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Drug ,Cancer Research ,media_common.quotation_subject ,Poly ADP ribose polymerase ,Mice, Nude ,Article ,Piperazines ,Olaparib ,Mice ,chemistry.chemical_compound ,In vivo ,Cell Line, Tumor ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Animals ,Humans ,media_common ,Ovarian Neoplasms ,business.industry ,Triazoles ,medicine.disease ,In vitro ,High-Throughput Screening Assays ,Disease Models, Animal ,Hydrazines ,Oncology ,chemistry ,Cell culture ,PARP inhibitor ,Cancer research ,Phthalazines ,Female ,Ovarian cancer ,business - Abstract
CRM1 inhibitors have demonstrated antitumor effects in ovarian and other cancers; however, rational combinations are largely unexplored. We performed a high-throughput drug library screen to identify drugs that might combine well with selinexor in ovarian cancer. Next, we tested the combination of selinexor with the top hit from the drug screen in vitro and in vivo. Finally, we assessed for mechanisms underlying the identified synergy using reverse phase protein arrays (RPPA). The drug library screen assessing 688 drugs identified olaparib (a PARP inhibitor) as the most synergistic combination with selinexor. Synergy was further demonstrated by MTT assays. In the A2780luc ip1 mouse model, the combination of selinexor and olaparib yielded significantly lower tumor weight and fewer tumor nodules compared with the control group (P < 0.04 and P < 0.03). In the OVCAR5 mouse model, the combination yielded significantly fewer nodules (P = 0.006) and markedly lower tumor weight compared with the control group (P = 0.059). RPPA analysis indicated decreased expression of DNA damage repair proteins and increased expression of tumor suppressor proteins in the combination treatment group. Collectively, our preclinical findings indicate that combination with selinexor to expand the utility and efficacy of PARP inhibitors in ovarian cancer warrants further exploration.
- Published
- 2021
49. The Clinical Challenges, Trials, and Errors of Combatting Poly(ADP-Ribose) Polymerase Inhibitors Resistance
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Melissa M. Pham, Emily Hinchcliff, Monica Avila, and Shannon N. Westin
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Cancer Research ,Oncology - Published
- 2021
50. Multicenter Phase II Trial of the WEE1 Inhibitor Adavosertib in Refractory Solid Tumors Harboring
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Siqing, Fu, Shuyang, Yao, Yuan, Yuan, Rebecca A, Previs, Anthony D, Elias, Richard D, Carvajal, Thomas J, George, Ying, Yuan, Lihou, Yu, Shannon N, Westin, Yan, Xing, Ecaterina E, Dumbrava, Daniel D, Karp, Sarina A, Piha-Paul, Apostolia M, Tsimberidou, Jordi Rodon, Ahnert, Naoko, Takebe, Karen, Lu, Khandan, Keyomarsi, and Funda, Meric-Bernstam
- Abstract
Preclinical cancer models harboringPatients aged ≥ 18 years with measurable disease and refractory solid tumors harboringThirty patients were enrolled. The median follow-up duration was 9.9 months. Eight patients had partial responses (PRs), and three had stable disease (SD) ≥ 6 months, with an ORR of 27% (95% CI, 12 to 46), a SD ≥ 6 months/PR rate of 37% (95% CI, 20 to 56), a median progression-free survival duration of 4.1 months (95% CI, 1.8 to 6.4), and a median overall survival duration of 9.9 months (95% CI, 4.8 to 15). Fourteen patients with epithelial ovarian cancer showed an ORR of 36% (95% CI, 13 to 65) and SD ≥ 6 months/PR of 57% (95% CI, 29 to 82), a median progression-free survival duration of 6.3 months (95% CI, 2.4 to 10.2), and a median overall survival duration of 14.9 months (95% CI, 8.9 to 20.9). Common treatment-related toxicities were GI, hematologic toxicities, and fatigue.Adavosertib monotherapy demonstrates a manageable toxicity profile and promising clinical activity in refractory solid tumors harboring
- Published
- 2022
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