15 results on '"Suresh S Ramalingam"'
Search Results
2. Therapeutic efficacy of the novel SHP2 degrader SHP2-D26, alone or in combination, against lung cancer is associated with modulation of p70S6K/S6, Bim and Mcl-1
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Yunfu Deng, Guangzhi Ma, Karin A. Vallega, Dongsheng Wang, Mingliang Wang, Changwei Wang, Shaomeng Wang, Suresh S. Ramalingam, and Shi-Yong Sun
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ErbB Receptors ,Cancer Research ,Lung Neoplasms ,Drug Resistance, Neoplasm ,Carcinoma, Non-Small-Cell Lung ,Cell Line, Tumor ,Mutation ,Humans ,Ribosomal Protein S6 Kinases, 70-kDa ,Molecular Medicine ,Protein Kinase Inhibitors ,Molecular Biology - Abstract
SHP2, a protein tyrosine phosphatase, plays a critical role in fully activating oncogenic signaling pathways such as Ras/MAPK downstream of cell surface tyrosine receptors (e.g., EGFR), which are often activated in human cancers, and thus has emerged as an attractive cancer therapeutic target. This study focused on evaluating the therapeutic potential of the novel SHP2 degrader, SHP2-D26 (D26), either alone or in combination, against non-small cell lung cancer (NSCLC) cells. While all tested NSCLC cell lines responded to D26 with IC
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- 2022
3. Candidate mechanisms of acquired resistance to first-line osimertinib in EGFR-mutated advanced non-small cell lung cancer
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Juliann Chmielecki, Jhanelle E. Gray, Ying Cheng, Yuichiro Ohe, Fumio Imamura, Byoung Chul Cho, Meng-Chih Lin, Margarita Majem, Riyaz Shah, Yuri Rukazenkov, Alexander Todd, Aleksandra Markovets, J. Carl Barrett, Ryan J. Hartmaier, and Suresh S. Ramalingam
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Multidisciplinary ,General Physics and Astronomy ,General Chemistry ,General Biochemistry, Genetics and Molecular Biology - Abstract
Osimertinib, an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), potently and selectively inhibits EGFR-TKI-sensitizing and EGFR T790M resistance mutations. In the Phase III FLAURA study (NCT02296125), first-line osimertinib improved outcomes vs comparator EGFR-TKIs in EGFRm advanced non-small cell lung cancer. This analysis identifies acquired resistance mechanisms to first-line osimertinib. Next-generation sequencing assesses circulating-tumor DNA from paired plasma samples (baseline and disease progression/treatment discontinuation) in patients with baseline EGFRm. No EGFR T790M-mediated acquired resistance are observed; most frequent resistance mechanisms are MET amplification (n = 17; 16%) and EGFR C797S mutations (n = 7; 6%). Future research investigating non-genetic acquired resistance mechanisms is warranted.
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- 2023
4. Analysis of acquired resistance mechanisms to osimertinib in patients with EGFR-mutated advanced non-small cell lung cancer from the AURA3 trial
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Juliann Chmielecki, Tony Mok, Yi-Long Wu, Ji-Youn Han, Myung-Ju Ahn, Suresh S. Ramalingam, Thomas John, Isamu Okamoto, James Chih-Hsin Yang, Frances A. Shepherd, Krishna C. Bulusu, Gianluca Laus, Barbara Collins, J. Carl Barrett, Ryan J. Hartmaier, and Vassiliki Papadimitrakopoulou
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Multidisciplinary ,General Physics and Astronomy ,General Chemistry ,General Biochemistry, Genetics and Molecular Biology - Abstract
Osimertinib, an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), potently and selectively inhibits EGFR-TKI-sensitizing and EGFR T790M resistance mutations. This analysis evaluates acquired resistance mechanisms to second-line osimertinib (n = 78) in patients with EGFR T790M advanced non-small cell lung cancer (NSCLC) from AURA3 (NCT02151981), a randomized phase 3 study comparing osimertinib with chemotherapy. Plasma samples collected at baseline and disease progression/treatment discontinuation are analyzed using next-generation sequencing. Half (50%) of patients have undetectable plasma EGFR T790M at disease progression and/or treatment discontinuation. Fifteen patients (19%) have >1 resistance-related genomic alteration; MET amplification (14/78, 18%) and EGFR C797X mutation (14/78, 18%).
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- 2023
5. Durvalumab with platinum-pemetrexed for unresectable pleural mesothelioma: survival, genomic and immunologic analyses from the phase 2 PrE0505 trial
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Dipika Singh, Hedy L. Kindler, Valsamo Anagnostou, Thomas Purcell, Hossein Borghaei, Julie R. Brahmer, Rachel Karchin, Arkadiusz Z. Dudek, Rafael Santana-Davila, Archana Balan, Z. Sun, Sampriti Thapa, Xiaoshan M. Shao, Victor E. Velculescu, Zineb Belcaid, Drew M. Pardoll, Suresh S. Ramalingam, Noushin Niknafs, Suzanne E. Dahlberg, Peter B. Illei, Patrick M. Forde, Christopher Cherry, James R. White, Kellie N. Smith, Hok Yee Chan, Mara Lanis, and I K Ashok Sivakumar
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Adult ,Male ,Mesothelioma ,Oncology ,medicine.medical_specialty ,Durvalumab ,DNA Repair ,medicine.medical_treatment ,Cancer immunotherapy ,Pemetrexed ,Article ,Phase II trials ,General Biochemistry, Genetics and Molecular Biology ,Carboplatin ,Antineoplastic Agents, Immunological ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Cancer genomics ,Clinical endpoint ,medicine ,Humans ,Genetic Predisposition to Disease ,Germ-Line Mutation ,Aged ,Nucleic Acid Synthesis Inhibitors ,Aged, 80 and over ,Cisplatin ,Chemotherapy ,business.industry ,Tumor Suppressor Proteins ,Mesothelioma, Malignant ,Antibodies, Monoclonal ,Cancer ,General Medicine ,Middle Aged ,medicine.disease ,Progression-Free Survival ,Immune checkpoint ,Tumour immunology ,Female ,business ,Ubiquitin Thiolesterase ,medicine.drug - Abstract
Mesothelioma is a rare and fatal cancer with limited therapeutic options until the recent approval of combination immune checkpoint blockade. Here we report the results of the phase 2 PrE0505 trial (NCT02899195) of the anti-PD-L1 antibody durvalumab plus platinum-pemetrexed chemotherapy for 55 patients with previously untreated, unresectable pleural mesothelioma. The primary endpoint was overall survival compared to historical control with cisplatin and pemetrexed chemotherapy; secondary and exploratory endpoints included safety, progression-free survival and biomarkers of response. The combination of durvalumab with chemotherapy met the pre-specified primary endpoint, reaching a median survival of 20.4 months versus 12.1 months with historical control. Treatment-emergent adverse events were consistent with known side effects of chemotherapy, and all adverse events due to immunotherapy were grade 2 or lower. Integrated genomic and immune cell repertoire analyses revealed that a higher immunogenic mutation burden coupled with a more diverse T cell repertoire was linked to favorable clinical outcome. Structural genome-wide analyses showed a higher degree of genomic instability in responding tumors of epithelioid histology. Patients with germline alterations in cancer predisposing genes, especially those involved in DNA repair, were more likely to achieve long-term survival. Our findings indicate that concurrent durvalumab with platinum-based chemotherapy has promising clinical activity and that responses are driven by the complex genomic background of malignant pleural mesothelioma., In a phase 2 trial, the combination of chemotherapy with durvalumab, an anti-PD-L1 antibody, exhibited promising clinical activity in patients with previously untreated, unresectable mesothelioma, with additional analyses providing insights into genomic and immunologic features potentially associated with response.
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- 2021
6. Spatially variant immune infiltration scoring in human cancer tissues
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Mayar Allam, Thomas Hu, Jeongjin Lee, Jeffrey Aldrich, Sunil S. Badve, Yesim Gökmen-Polar, Manali Bhave, Suresh S. Ramalingam, Frank Schneider, and Ahmet F. Coskun
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Cancer Research ,Oncology - Abstract
The Immunoscore is a method to quantify the immune cell infiltration within cancers to predict the disease prognosis. Previous immune profiling approaches relied on limited immune markers to establish patients’ tumor immunity. However, immune cells exhibit a higher-level complexity that is typically not obtained by the conventional immunohistochemistry methods. Herein, we present a spatially variant immune infiltration score, termed as SpatialVizScore, to quantify immune cells infiltration within lung tumor samples using multiplex protein imaging data. Imaging mass cytometry (IMC) was used to target 26 markers in tumors to identify stromal, immune, and cancer cell states within 26 human tissues from lung cancer patients. Unsupervised clustering methods dissected the spatial infiltration of cells in tissue using the high-dimensional analysis of 16 immune markers and other cancer and stroma enriched labels to profile alterations in the tumors’ immune infiltration patterns. Spatially resolved maps of distinct tumors determined the spatial proximity and neighborhoods of immune-cancer cell pairs. These SpatialVizScore maps provided a ranking of patients’ tumors consisting of immune inflamed, immune suppressed, and immune cold states, demonstrating the tumor’s immune continuum assigned to three distinct infiltration score ranges. Several inflammatory and suppressive immune markers were used to establish the cell-based scoring schemes at the single-cell and pixel-level, depicting the cellular spectra in diverse lung tissues. Thus, SpatialVizScore is an emerging quantitative method to deeply study tumor immunology in cancer tissues.
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- 2022
7. Correction to: Osimertinib for EGFR-Mutant Non-Small-Cell Lung Cancer Central Nervous System Metastases: Current Evidence and Future Perspectives on Therapeutic Strategies
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Sanjay Popat, Myung-Ju Ahn, Simon Ekman, Natasha B. Leighl, Suresh S. Ramalingam, Thanyanan Reungwetwattana, Shankar Siva, Masahiro Tsuboi, Yi-Long Wu, and James Chih-Hsin Yang
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Cancer Research ,Oncology ,Pharmacology (medical) - Published
- 2023
8. Correction to: Therapeutic efficacy of the novel SHP2 degrader SHP2-D26, alone or in combination, against lung cancer is associated with modulation of p70S6K/S6, Bim and Mcl-1
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Yunfu Deng, Guangzhi Ma, Karin A. Vallega, Dongsheng Wang, Mingliang Wang, Changwei Wang, Shaomeng Wang, Suresh S. Ramalingam, and Shi-Yong Sun
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Cancer Research ,Molecular Medicine ,Molecular Biology - Published
- 2022
9. Sotorasib effective in KRAS-mutant NSCLC
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Ferdinandos, Skoulidis, Bob T, Li, Grace K, Dy, Timothy J, Price, Gerald S, Falchook, Jürgen, Wolf, Antoine, Italiano, Martin, Schuler, Hossein, Borghaei, Fabrice, Barlesi, Terufumi, Kato, Alessandra, Curioni-Fontecedro, Adrian, Sacher, Alexander, Spira, Suresh S, Ramalingam, Toshiaki, Takahashi, Benjamin, Besse, Abraham, Anderson, Agnes, Ang, Qui, Tran, Omar, Mather, Haby, Henary, Gataree, Ngarmchamnanrith, Gregory, Friberg, Vamsidhar, Velcheti, and Ramaswamy, Govindan
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Adult ,Male ,2019-20 coronavirus outbreak ,Lung Neoplasms ,Coronavirus disease 2019 (COVID-19) ,Pyridines ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Mutant ,Antineoplastic Agents ,medicine.disease_cause ,B7-H1 Antigen ,Piperazines ,Article ,Proto-Oncogene Proteins p21(ras) ,Carcinoma, Non-Small-Cell Lung ,medicine ,Humans ,Aged ,Aged, 80 and over ,business.industry ,Middle Aged ,Virology ,Progression-Free Survival ,Pyrimidines ,Oncology ,Mutation ,Female ,KRAS ,business ,Biomarkers - Abstract
BACKGROUND: Sotorasib showed anticancer activity in patients with KRAS p.G12C–mutated advanced solid tumors in a phase 1 study, and particularly promising anticancer activity was observed in a subgroup of patients with non–small-cell lung cancer (NSCLC). METHODS: In a single-group, phase 2 trial, we investigated the activity of sotorasib, administered orally at a dose of 960 mg once daily, in patients with KRAS p.G12C–mutated advanced NSCLC previously treated with standard therapies. The primary end point was objective response (complete or partial response) according to independent central review. Key secondary end points included duration of response, disease control (defined as complete response, partial response, or stable disease), progression-free survival, overall survival, and safety. Exploratory biomarkers were evaluated for their association with response to sotorasib therapy. RESULTS: Among the 126 enrolled patients, the majority (81.0%) had previously received both platinum-based chemotherapy and inhibitors of programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1). According to central review, 124 patients had measurable disease at baseline and were evaluated for response. An objective response was observed in 46 patients (37.1%; 95% confidence interval [CI], 28.6 to 46.2), including in 4 (3.2%) who had a complete response and in 42 (33.9%) who had a partial response. The median duration of response was 11.1 months (95% CI, 6.9 to could not be evaluated). Disease control occurred in 100 patients (80.6%; 95% CI, 72.6 to 87.2). The median progression-free survival was 6.8 months (95% CI, 5.1 to 8.2), and the median overall survival was 12.5 months (95% CI, 10.0 to could not be evaluated). Treatment-related adverse events occurred in 88 of 126 patients (69.8%), including grade 3 events in 25 patients (19.8%) and a grade 4 event in 1 (0.8%). Responses were observed in subgroups defined according to PD-L1 expression, tumor mutational burden, and co-occurring mutations in STK11, KEAP1, or TP53. CONCLUSIONS: In this phase 2 trial, sotorasib therapy led to a durable clinical benefit without new safety signals in patients with previously treated KRAS p.G12C–mutated NSCLC. (Funded by Amgen and the National Institutes of Health; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.)
- Published
- 2021
10. Acetylation regulates ribonucleotide reductase activity and cancer cell growth
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Madhusmita Behera, David S. Yu, Guo Chen, Duc M. Duong, Kurt Warncke, Walter J. Curran, Michael Lammers, Paul W. Doetsch, Haian Fu, Xingming Deng, Youwei Sun, Suresh S. Ramalingam, and Yin Luo
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DNA Replication ,0301 basic medicine ,Ribonucleoside Diphosphate Reductase ,DNA damage ,Science ,Protein subunit ,General Physics and Astronomy ,02 engineering and technology ,SIRT2 ,Article ,General Biochemistry, Genetics and Molecular Biology ,S Phase ,03 medical and health sciences ,Sirtuin 2 ,Cell Line, Tumor ,Ribonucleotide Reductases ,DNA metabolism ,Humans ,KAT7 ,lcsh:Science ,Histone Acetyltransferases ,Multidisciplinary ,DNA synthesis ,Chemistry ,Cell Cycle ,Acetylation ,General Chemistry ,021001 nanoscience & nanotechnology ,DNA Replication Fork ,3. Good health ,Cell biology ,Gene Expression Regulation, Neoplastic ,Cell Transformation, Neoplastic ,030104 developmental biology ,Ribonucleotide reductase ,Enzyme mechanisms ,Camptothecin ,lcsh:Q ,0210 nano-technology ,DNA Damage - Abstract
Ribonucleotide reductase (RNR) catalyzes the de novo synthesis of deoxyribonucleoside diphosphates (dNDPs) to provide dNTP precursors for DNA synthesis. Here, we report that acetylation and deacetylation of the RRM2 subunit of RNR acts as a molecular switch that impacts RNR activity, dNTP synthesis, and DNA replication fork progression. Acetylation of RRM2 at K95 abrogates RNR activity by disrupting its homodimer assembly. RRM2 is directly acetylated by KAT7, and deacetylated by Sirt2, respectively. Sirt2, which level peak in S phase, sustains RNR activity at or above a threshold level required for dNTPs synthesis. We also find that radiation or camptothecin-induced DNA damage promotes RRM2 deacetylation by enhancing Sirt2–RRM2 interaction. Acetylation of RRM2 at K95 results in the reduction of the dNTP pool, DNA replication fork stalling, and the suppression of tumor cell growth in vitro and in vivo. This study therefore identifies acetylation as a regulatory mechanism governing RNR activity., Ribonucleotide reductase (RNR) catalyzes the de novo synthesis of deoxyribonucleoside diphosphates to provide dNTP precursors for DNA synthesis. Here the authors show that the availability of dNTPs, DNA replication, and cellular proliferation, are modulated by acetylation and deacetylation of RRM2 by KAT7 and Sirt2 respectively.
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- 2019
11. Role of Ku70 in deubiquitination of Mcl-1 and suppression of apoptosis
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Maohua Xie, Bin Wang, Taofeek K. Owonikoko, Ya Wang, Xingming Deng, Suresh S. Ramalingam, Runzhao Li, Walter J. Curran, and Fadlo R. Khuri
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Cell Survival ,Mice, Nude ,Antineoplastic Agents ,Apoptosis ,Piperazines ,Nitrophenols ,Mice ,Ubiquitin ,immune system diseases ,hemic and lymphatic diseases ,Animals ,Humans ,Protein Interaction Domains and Motifs ,Ku Autoantigen ,neoplasms ,Molecular Biology ,Sulfonamides ,Original Paper ,Gene knockdown ,Ku70 ,biology ,Protein Stability ,Endoplasmic reticulum ,Biphenyl Compounds ,HEK 293 cells ,Ubiquitination ,Antigens, Nuclear ,Cell Biology ,HCT116 Cells ,Staurosporine ,Xenograft Model Antitumor Assays ,Molecular biology ,Transport protein ,Cell biology ,DNA-Binding Proteins ,Protein Transport ,HEK293 Cells ,biology.protein ,Myeloid Cell Leukemia Sequence 1 Protein ,Half-Life ,Deubiquitination - Abstract
Mcl-1 is a unique antiapoptotic Bcl2 family member with a short half-life due to its rapid turnover through ubiquitination. We discovered that Ku70, a DNA double-strand break repair protein, functions as a deubiquitinase to stabilize Mcl-1. Ku70 knockout in mouse embryonic fibroblast (MEF) cells or depletion from human lung cancer H1299 cells leads to the accumulation of polyubiquitinated Mcl-1 and a reduction in its half-life and protein expression. Conversely, expression of exogenous Ku70 in Ku70(-/-) MEF cells restores Mcl-1 expression. Subcellular fractionation indicates that Ku70 extensively colocalizes with Mcl-1 in mitochondria, endoplasmic reticulum and nucleus in H1299 cells. Ku70 directly interacts with Mcl-1 via its C terminus (that is, aa 536-609), which is required and sufficient for deubiquitination and stabilization of Mcl-1, leading to suppression of apoptosis. Purified Ku70 protein directly deubiquitinates Mcl-1 by removing K48-linked polyubiquitin chains. Ku70 knockdown not only promotes Mcl-1 turnover but also enhances antitumor efficacy of the BH3-mimetic ABT-737 in human lung cancer xenografts. These findings identify Ku70 as a novel Mcl-1 deubiquitinase that could be a potential target for cancer therapy by manipulating Mcl-1 deubiquitination.
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- 2014
12. A phase 1 Bayesian dose selection study of bortezomib and sunitinib in patients with refractory solid tumor malignancies
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Dong M. Shin, Bassel F. El-Rayes, Fadlo R. Khuri, Mourad Tighiouart, Colleen Lewis, Michael Fanucchi, Andre Rogatko, R. D. Harvey, P Nadella, Suresh S. Ramalingam, A. Akintayo, John S. Kauh, Zhengjia Chen, and Taofeek K. Owonikoko
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Adult ,Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Indoles ,Maximum Tolerated Dose ,Short Communication ,sunitinib ,Phase 1 ,Pharmacology ,urologic and male genital diseases ,Bayesian ,Drug Administration Schedule ,Refractory ,immune system diseases ,Neoplasms ,hemic and lymphatic diseases ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Pyrroles ,In patient ,Thyroid Neoplasms ,Solid tumor ,Aged ,Aged, 80 and over ,Bortezomib ,Sunitinib ,business.industry ,bortezomib ,Bayes Theorem ,Middle Aged ,Boronic Acids ,female genital diseases and pregnancy complications ,Pyrazines ,Maximum tolerated dose ,Female ,business ,EWOC ,medicine.drug ,Dose selection - Abstract
Background: This phase 1 trial utilising a Bayesian continual reassessment method evaluated bortezomib and sunitinib to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and recommended doses of the combination. Methods: Patients with advanced solid organ malignancies were enrolled and received bortezomib weekly with sunitinib daily for 4 weeks, every 6 weeks. Initial doses were sunitinib 25 mg and bortezomib 1 mg m−2. Cohort size and dose level estimation was performed utilising the Escalation with Overdose Control (EWOC) adaptive method. Seven dose levels were evaluated; initially, sunitinib was increased to a goal dose of 50 mg with fixed bortezomib, then bortezomib was increased. Efficacy assessment occurred after each cycle using RECIST criteria. Results: Thirty patients were evaluable. During sunitinib escalation, DLTs of grade 4 thrombocytopenia (14%) and neutropenia (6%) at sunitinib 50 mg and bortezomib 1.3 mg m−2 were seen. Subsequent experience showed tolerability and activity for sunitinib 37.5 mg and bortezomib 1.9 mg m−2. Common grade 3/4 toxicities were neutropenia, thrombocytopenia, hypertension, and diarrhoea. The recommended doses for further study are bortezomib 1.9 mg m−2 and sunitinib 37.5 mg. Four partial responses were seen. Stable disease >6 months was noted in an additional six patients. Conclusion: Bortezomib and sunitinib are well tolerated and have anticancer activity, particularly in thyroid cancer. A phase 2 study of this combination in thyroid cancer patients is planned.
- Published
- 2013
13. The Biology and Clinical Features of Non–small Cell Lung Cancers with EML4-ALK Translocation
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Rathi N. Pillai and Suresh S. Ramalingam
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Lung Neoplasms ,Oncogene Proteins, Fusion ,Pyridines ,Ganetespib ,non-small cell lung cancer (NSCLC) ,Translocation, Genetic ,Crizotinib ,Carcinoma, Non-Small-Cell Lung ,hemic and lymphatic diseases ,Heat shock protein ,medicine ,Humans ,Anaplastic lymphoma kinase ,Protein Kinase Inhibitors ,Clinical Trials as Topic ,Lung ,Kinase ,business.industry ,medicine.disease ,respiratory tract diseases ,medicine.anatomical_structure ,Oncology ,Drug Resistance, Neoplasm ,Cancer research ,Pyrazoles ,Non small cell ,business ,medicine.drug - Abstract
The anaplastic lymphoma kinase (ALK) acts as a dominant oncogenic driver following chromosomal rearrangements in certain cancers including non-small cell lung cancer (NSCLC). NSCLC with ALK translocation occurs in a specific subset of patients and results in unique clinical features. Crizotinib is a small molecule inhibitor of ALK kinase that has recently been approved by the FDA for the treatment of patients with ALK-positive NSCLC. Treatment with crizotinib results in clinical benefit rate of 85%-90% and a median progression-free survival of 9-10 months for this molecular subset of patients. Ongoing studies will define the impact of crizotinib on overall survival and provide insights into the resistance mechanisms and potential activation of alternate pathways. Heat shock protein 90 inhibitors also appear promising in the treatment of ALK-positive NSCLC patients, based on early results. This article reviews the characteristics, treatment, and ongoing research in patients with ALK-positive NSCLC.
- Published
- 2012
14. A phase 1 study of BMS-275183, a novel oral analogue of paclitaxel given on a daily schedule to patients with advanced malignancies
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Manuel Valdivieso, Leila Alland, Merrill J. Egorin, Patricia LoRusso, Elisabeth I. Heath, Tatiana Besse-Hamer, Fatima Cardoso, Suresh S. Ramalingam, Teresa Has, Ahmad Awada, Chandra P. Belani, and Xiaofei Zhou
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Bridged-Ring Compounds ,Male ,medicine.medical_specialty ,Neutropenia ,Nausea ,Administration, Oral ,Antineoplastic Agents ,Gastroenterology ,Drug Administration Schedule ,Sepsis ,chemistry.chemical_compound ,Pharmacokinetics ,Oral administration ,Neoplasms ,Internal medicine ,medicine ,Humans ,Pharmacology (medical) ,Dosing ,Adverse effect ,Aged ,Pharmacology ,Dose-Response Relationship, Drug ,business.industry ,Middle Aged ,medicine.disease ,Surgery ,Treatment Outcome ,Oncology ,Paclitaxel ,chemistry ,Tolerability ,Female ,medicine.symptom ,business - Abstract
Purpose BMS-275183 is an oral C-4 methyl carbonate analogue of paclitaxel that has the same mechanism of action, stabilization of tubulin polymerization. The present study was designed to: (i) assess the safety and tolerability of BMS-275183, and (ii) determine a suitable Phase II dose of BMS-275183 when given on a continuous daily schedule to patients with advanced solid tumor(s). Methods This was a multi-institutional, open-label, Phase I, single-arm dose escalation study in which cohorts of eligible patients with advanced malignancies were treated with BMS-275183 orally on a continuous daily schedule. The starting dose level was 6 mg/m2/day administered once daily. Cohorts of 3 patients were treated at each dose level provided no dose-limiting toxicities (DLTs) were observed. Each cycle of treatment lasted 28 days. Results Twenty patients were enrolled in dose cohorts ranging from the initial dose level of 6 mg/m2/day to 18 mg/m2/day. Overall, the most frequent (>20% of patients) treatment-related adverse events (AEs) were nausea (40%), constipation (20%), diarrhea (20%), and fatigue (20%). There were 2 fatal events of neutropenic sepsis one each at the 15 mg/m2/day and 18 mg/m2/day dose level, respectively. There were no objective responses; 4 of 20 patients experienced stable disease. Pharmacokinetic data indicated no clear correlation between dose and exposure following daily oral administration of BMS-275183 doses between 6 and 18 mg/m2. Substantial inter-patient variability was observed, and high drug exposure was associated with fatal neutropenic sepsis. Conclusions BMS-275183 is a novel oral analogue of paclitaxel with high inter-patient variability in exposure. The lack of evidence of clinical benefit and the occurrence of two fatal events of neutropenic sepsis, coupled with high drug exposure, argues against further evaluation of BMS-275183 on a daily dosing schedule.
- Published
- 2010
15. The Role of Targeted Agents in the Treatment of Elderly Patients with Non-Small Cell Lung Cancer (NSCLC)
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Suresh S. Ramalingam and Taofeek K. Owonikoko
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Vascular Endothelial Growth Factor A ,Oncology ,medicine.medical_specialty ,Lung Neoplasms ,Bevacizumab ,Population ,non-small cell lung cancer (NSCLC) ,Angiogenesis Inhibitors ,Pharmacology ,Antibodies, Monoclonal, Humanized ,Erlotinib Hydrochloride ,Gefitinib ,Carcinoma, Non-Small-Cell Lung ,Internal medicine ,Humans ,Medicine ,Pharmacology (medical) ,Enzyme Inhibitors ,education ,Aged ,education.field_of_study ,Epidermal Growth Factor ,Cetuximab ,Performance status ,business.industry ,Age Factors ,Antibodies, Monoclonal ,Protein-Tyrosine Kinases ,medicine.disease ,ErbB Receptors ,Clinical trial ,Quinazolines ,Erlotinib ,business ,Signal Transduction ,medicine.drug - Abstract
The introduction of targeted biological agents represents the most promising approach to improve the disease control and outcome for patients with non-small cell lung cancer. The epidermal growth factor and the vascular endothelial growth factor signaling pathways have been successfully targeted using both orally administered small molecule tyrosine kinase inhibitors and monoclonal antibodies, with associated improvement in overall survival. Although the trials that established the efficacy of these agents allowed the enrollment of patients older than 70 years, the elderly patients constituted the minority. Given the stringent enrolment criteria in terms of organ function and performance status for most clinical trials, the elderly patients on clinical trials are not entirely representative of the overall elderly patient population. Therefore, the applicability of these data to the overall patient population deserves critical appraisal in the absence of trials dedicated specifically to the elderly. Preplanned and unplanned subset analysis of registration trial data is becoming increasingly common as a substitute measure to provide valuable information to guide the use of targeted agents in the elderly. Using this approach, it has been demonstrated that elderly patients are able to tolerate targeted biological therapies but suffer increased rate of toxicities. However, they derive benefit from such agents when they are carefully selected and have their drug doses adjusted appropriately to minimize potential toxicities. This article reviews the use of targeted agents for the treatment of NSCLC in elderly patients.
- Published
- 2008
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