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Background: Novel anti-PSMA (prostate-specific membrane antigen) targeted therapies have exhibited encouraging antitumor activity in prostate cancer and most non-prostate solid tumors express PSMA in tumor neovasculature. ARX517 is an antibody drug conjugate composed of a fully humanized anti-PSMA monoclonal antibody linked to pAF-AS269, a potent microtubule inhibitor. Upon binding to PSMA on the surface of cancer cells, ARX517 is internalized and pAF-AS269 is released following lysosomal metabolism. Methods: This Phase 1, dose-escalation and dose-expansion study is evaluating the safety, pharmacokinetics, and preliminary anti-tumor activity of ARX517 in adults with prostate cancer or other solid tumors whose disease is resistant or refractory to standard therapies. Patients must have metastatic castration-resistant prostate cancer refractory to standard therapies, including abiraterone, darolutamide, apalutamide or enzalutamide and progression by Prostate Cancer Working Group criteria. Non-prostate advanced solid tumors must be pathologically confirmed, metastatic, or unresectable solid tumors that have disease progression despite at least 1 prior standard of care systemic treatment and have no satisfactory treatment alternatives. All patients must have adequate organ function and any brain metastasis must demonstrate radiographic stability. Exploratory pharmacodynamic assessment includes PSMA-PET/CT imaging, which is optional for low dose cohorts but required starting at 1.4 mg/kg dose. Dose-escalation will consist of ascending dose levels of ARX517 administered as a single agent and will use a i3+3 design. The number of subjects in the dose-expansion will be based on the number of doses to be expanded for further evaluation of safety, PK, and clinical activity. Through dose levels one and two, no dose limiting toxicities have been observed. Ascending dose levels of ARX517 as a single agent will be administered until the recommended Phase 2 dose or maximum tolerated dose is determined. Status: ARX517-2011 began recruiting patients in July 2021 and as of January 2022 has completed enrollment in the 3rd cohort of dose-escalation. Citation Format: Russell K. Pachynski, Luke Nordquist, Michael T. Schweizer, John Shen, Nabil Adra, Mehmet A. Bilen, Zachery R. Reichert, Rahul Aggarwal, Bilal A. Siddiqui, Matt Li, Dong Xu, Richard Huhn, Darryl Z. L'Heureux, Jinchun Yan, Ying Buechler, Sulan Yao, John Simitzi, Wenge Shi, Shawn Zhang, Scott T. Tagawa. A phase 1 dose-escalation and dose-expansion study to evaluate the safety, pharmacokinetics, and anti- tumor activity of ARX517 in subjects with advanced solid tumors resistant or refractory to standard therapies (APEX-01 trial, NCT04662580) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT211.

Background: Tumor infiltrating immune cells have a clear prognostic benefit in many tumor types. Immune variables have independently improved prognostication in various cancer types, with tumor-infiltrating lymphocytes (TILs) more accurately predicting patient survival than currently employed methods. This has been shown using the Immuno-score, which predicts disease progression in colorectal cancer based on CD8 T cell infiltration. Many recent studies have also highlighted similar observations in other cancers, including breast cancer, lung cancer, and melanoma. These observations raise the question of whether the level of CD8 T cell infiltration into renal cell tumors may also predict patient survival, and more fundamentally, why some patients may mount a strong immune response to their tumors and others do not. Methods: Tumor tissue was collected from 68 renal cell carcinoma (RCC) patients undergoing surgery at Emory University Hospital. Patients had a minimum follow up time of 24 months. Intraoperative tumor samples were processed and analyzed by flow cytometry and immunofluorescence. Results: The proportion of CD8 TILs, measured by flow cytometry, was found to vary widely in RCC patients. This CD8 T cell response is independent of standard risk assessment tools, tumor size, pathology, and patient demographics. Significantly, an increasing percent of tumor CD8 T cells is associated with improved cancer-specific survival in these patients, and this association is particularly strong in a small cohort of stage III patients. The phenotype and functional capacity of TILs were examined, and presence of a stem-like CD8 T cell—that can proliferate and differentiate—was required to generate a strong anti-tumor Tcell response. When this stem-like T cell is lost, there is a poor anti-tumor immune response and patients experience progressive disease. Flow cytometry analysis revealed that the number of dendritic cells in the tumor correlates with T cell infiltration, and immunofluorescence image analysis showed that stem-like T cells reside in areas of high antigen-presenting cell density. Tumors with poor T cell infiltration lack APC density, suggesting that an antigen presenting niche is required for a strong T cell response. Conclusions: Measuring CD8 T cell infiltration in RCC predicts cancer-specific survival, particularly in patients with advanced disease. As this patient population is one for whom improved prognostication is a critical clinical goal, this study represents an opportunity to inform future prognostic measures and to direct reduction or intensification of therapy. The T cell response was found to be maintained by a population of cells, which harbor both proliferative and differentiation capacity. These stem-like cells require a supportive niche inside the tumor in order to persist, and without this support, the T cell response collapses, resulting in disease progression. Citation Format: Caroline S. Jansen, Nataliya Prokhnevska, Viraj A. Master, Jennifer W. Carlisle, Mehmet A. Bilen, Adriana M. Reyes, Haydn T. Kissick. CD8 T-cell infiltration into renal tumors requires a supportive antigen-presenting niche [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2700.

Prostate cancer is the second leading cause of cancer-related deaths among men in western countries. Majority of prostate tumors often evolves as metastatic castration-resistant prostate cancer (CRPC) following hormonal therapy. Metastatic prostate cancer is the major cause of mortalities from this disease. African-American (AA) men have the highest incidence and mortality rate compared to any other race such as Caucasian American (CA). Despite recent advances, the cellular and molecular mechanisms that contribute to this disparity are unknown, obstructing the development of an effective therapy for this disease. Genetic and epigenetic studies have indicated that the biology of prostate cancer in AA men is substantially different from CA. Here, we investigate the dopamine (DA) signaling to better understand the mechanism of prostate cancer disparity. Our analysis of the prostate cancer public data sets showed that the dopamine receptor (DR) genes were amplified in up to 18% prostate cancer clinical cases. We have demonstrated that the levels of DR transcripts were significantly higher in the metastatic prostate cancer cell lines with African genetic ancestry than CA counters. We also demonstrate that the efficacy of pimozide, a potent DRD inhibitor and an FDA-approved antipsychotic, on AA cells was significantly higher than CA cells. In addition, we have found that L-dopa, an immediate precursor of DA differentially regulates the growth of AA and CA prostate cancer cells in a dose dependent manner. We also found that carbidopa, a potent inhibitor of the dopa decarboxylase, suppressed prostate cancer cell growth by L-dopa and showed that carbidopa re-sensitized CRPC cell line to enzalutamide, a potent inhibitor of androgen receptor (AR) signaling. These observations suggest that DA/DR signaling plays a critical role in prostate cancer disparity, making the DA/DR-AR axis a viable therapeutic target to reduce disparities in cancer mortality. Citation Format: Isaiah R. Pickett, Ava M. Boston, Marwah M. Almathkour, Camille Ragin, Mehmet A. Bilen, Adeboye O. Osunkoya, Bekir Cinar. The role of dopamine signaling in prostate cancer disparities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1022.

Induction of new bone formation is frequently seen in the bone lesions from prostate cancer. However, whether osteogenesis is necessary for prostate tumor growth in bone is unknown. Recently, 2 xenografts, MDA-PCa-118b and MDA-PCa-133, were generated from prostate cancer bone metastases. When implanted subcutaneously in severe combined immunodeficient (SCID) mice, MDA-PCa-118b induced strong ectopic bone formation while MDA-PCa-133 did not. To identify the factors that are involved in bone formation, we compared the expression of secreted factors (secretome) from MDA-PCa-118b and MDA-PCa-133 by cytokine array. We found that the osteogenic MDA-PCa-118b xenograft expressed higher levels of bone morphogenetic protein BMP4 and several cytokines including interleukin-8, growth-related protein (GRO), and CCL2. We showed that BMP4 secreted from MDA-PCa-118b contributed to about a third of the osteogenic differentiation seen in MDA-PCa-118b tumors. The conditioned media from MDA-PCa-118b induced a higher level of osteoblast differentiation, which was significantly reduced by treatment with BMP4 neutralizing antibody or the small molecule BMP receptor 1 inhibitor LDN-193189. BMP4 did not elicit an autocrine effect on MDA-PCa-118b, which expressed low to undetectable levels of BMP receptors. Treatment of SCID mice bearing MDA-PCa-118b tumors with LDN-193189 significantly reduced tumor growth. Thus, these studies support a role of BMP4-mediated osteogenesis in the progression of prostate cancer in bone. Cancer Res; 71(15); 5194–203. ©2011 AACR.

Background: Optimal biomarkers for cancer pts treated with IO are currently lacking. Markers of inflammation, such as neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and platelet-to-lymphocyte ratio (PLR) are readily available and associated with poor outcomes. We investigated the association between these markers and CO in pts treated with IO. Methods: We conducted a retrospective review of 90 pts with advanced cancer treated on IO-based phase I trials at the Winship Cancer Institute of Emory University between 2009-2017. Baseline NLR, MLR, and PLR were treated as continuous variables and rescaled by their own standard deviation. Overall survival (OS) was measured from the first dose of IO to date of death or hospice referral. Progression-free survival (PFS) was determined from first dose of IO to clinical or radiographic progression or death. We defined clinical benefit (CB) as complete response, partial response, or stable disease. Univariate association (UVA) and multivariable analysis (MVA) were carried out using Cox proportional hazard model or logistic regression model. Baseline covariates included race, gender, ECOG PS, # of prior therapies, Royal Marsden Hospital (RMH) risk group, IO indication, and # of metastatic sites. Results: The median pt age was 63 years and most (59%) were men. The most common histologies were melanoma (33%) and GI cancers (22%). The majority (81%) were RMH good risk. 46% of pts had CB on IO. The median NLR, MLR, and PLR was 3.63, 0.48, and 182.65, respectively. Increased NLR, MLR, and PLR were all associated with worse OS, PFS, and chance of CB (Table 1). NLR, MLR and PLR are highly correlated to each other (Pearson correlation coefficients ≥ 0.8, all p < 0.0001). Conclusion: NLR, MLR, and PLR are strongly associated with CO in pts treated with IO. Prospective validation of these findings are warranted. Table 1: UVA and MVA of NLR, MRL, and PLR with CO OS PFSCBUVAMVAUVAMVAUVAMVAHR (CI)p-valueHR (CI)p-valueHR (CI)p-valueHR (CI)p-valueOR (CI)p-valueOR (CI)p-valueNLR1.37 (1.11-1.70)0.003*1.30 (1.02-1.66)0.031*1.42 (1.18-1.70) *statistically significant Citation Format: Dylan J. Martini, Yuan Liu, Colleen Lewis, Hannah Collins, Mehmet Akce, Haydn Kissick, Bradley C. Carthon, Walid L. Shaib, Olatunji B. Alese, Rathi Pillai, Conor E. Steuer, Christina Wu, David H. Lawson, Ragini Kudchadkar, Bassel El-Rayes, Viraj A. Master, Suresh Ramalingam, Taofeek K. Owonikoko, R Donald Harvey, Mehmet Asim Bilen. Blood based biomarkers and association with clinical outcome (CO) in advanced stage patients (pts) treated with immunotherapy (IO) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2607.

Cell adhesion molecules have been implicated in the colonization of cancer cells to distant organs. Prostate cancer (PCa) has a propensity to metastasize to bone, and cadherin-11, which is an osteoblast cadherin aberrantly expressed in PCa cells derived from bone metastases, has been shown to play a role in the metastasis of PCa cells to bone. However, the mechanism by which cadherin-11 is involved in this process is not known. Here, we show that expression of cadherin-11 in cadherin-11–negative C4-2B4 cells increases their spreading and intercalation into an osteoblast layer and also stimulates C4-2B4 cell migration and invasiveness. The downregulation of cadherin-11 in cadherin-11–expressing metastatic PC3 cells decreases cell motility and invasiveness. Further, both the juxtamembrane (JMD) and β-catenin binding domains (CBS) in the cytoplasmic tail of cadherin-11 are required for cell migration and invasion, but not spreading. Gene array analyses showed that several invasion-related genes, including MMP-7 and MMP-15, are upregulated in cadherin-11–expressing, but not in cad11-ΔJMD–expressing or cad11-ΔCBS–expressing, C4-2B4 cells. These observations suggest that cadherin-11 not only provides a physical link between PCa cells and osteoblasts but also increases PCa cell motility and invasiveness that may facilitate the metastatic colonization of PCa cells in bone. Cancer Res; 70(11); 4580–9. ©2010 AACR.

Background: Tolfenamic acid (TA) is Non-Steroidal Anti-Inflammatory Drug (NSAID) used to treat migraines. We previously reported that TA exhibits both chemopreventive (esophageal cancer) and chemotherapeutic activities in pancreatic, esophageal and colon cancer models that acts through down-regulating the expression of Sp proteins. Sp proteins regulate the expression of PSA, c-Met, survivin and other critical proteins that are important for cancer cell growth and metastasis. In this preclinical study, we have screened several new TA derivatives to evaluate their anti-cancer activity using prostate cancer model in order to identify robust candidates for the treatment of this and other cancers. Method: TA derivatives were selected based on their structural relationship with TA. Human prostate cancer cells (PC-3, DU-145 and LNcaP) were grown in the presence of control or various concentrations (25, 50 and 100 µM) of TA or selected analogs and cell proliferation was measured at 24, 48, and 72 h post-treatment using Cell Titer-Glo kit. Further studies were conducted with the two most active TA analogs. PC-3 cells were treated with vehicle or 50 µM TA analogs for 48 h and cell lystaes were prepared and used to evaluate the expression of Sp proteins (Sp1, Sp3 and Sp4), c-Met, Akt and survivin through Western blot analysis. Scratch (wound healing) assay was performed to determine the effect of these drugs on PC-3 cell migration. For in vivo studies, nude mice were injected with PC-3 cells into the right prostate and treated with vehicle or 50 mg/kg of one of the active TA analog/3 times a week and tumor growth was continuously monitored for 4 weeks. Results: Data showed a significant decrease in cell proliferation that was dose and time dependent. Screening the anti-proliferative activity, we identified at least two TA analogs that inhibited the cell viability more than original TA compound. TA and the two most active analogs significantly diminished the expression of Sp proteins, c-Met, phospho-Akt and survivin and inhibited the migration of cells. Interestingly, the effect of two TA analogs tested was greater than TA as reflected with their higher anti-proliferative activity. In vivo data showed a significant decrease (>50%) in tumor weight and volume after 4 weeks of treatment with selected TA analog confirming a strong correlation between in vitro and in vivo results. These results suggest that TA analogs inhibit prostate cancer cell proliferation, down-regulate the expression of c-Met and survivin, and disrupt phosphorylation of Akt through suppressing Sp proteins. Conclusion: Targeting key transcription factors such as Sp proteins using small molecules is a new strategy for the treatment of cancer including that of the prostate. In this interesting screening test, we have identified two promising active TA analogs for the potential implications in cancer therapy.Phase I clinical trial is in preparation for the lead compound (TA). Citation Format: Maen Abdelrahim, Mehmet Asim Bilen, Stephen Safe, Ala Abudayyeh. New tolfenamic acid's derivatives inhibit cancer cells growth and tumor progression: Pre-clinical studies update. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4532. doi:10.1158/1538-7445.AM2014-4532

Background: TKIs are a new class of novel cancer drugs that represent a significant advance in cancer therapy. TKI-induced thyroid dysfunction has been identified as an important but potentially manageable toxicity of targeted therapy. Relationship between new onset hypothyroidism and clinical response in patients with advanced cancers treated with TKI treatment was evaluated. Methods: We retrospectively reviewed 410 patients from 5 clinical trials treated with therapy that included at least one TKIstarting January, 2006. Patients with preexisting thyroid disease including thyroid cancer, hypo or hyperthyroidism were excluded. Analysis of 198 patients was performed. Response was determined by RECIST 1.0. Clinical benefit described as complete response or partial response or stable disease > 4 months. Multivariable Logistic Regression Analysis was used to correlate new onset hypothyroidism with clinical benefit. Results: The median age was 58 years (13 to 85); 56% of patients were female. 27% (53/198) of patients developed hypothyroidism after therapy. Clinical benefit rates were 51% in patients with new onset hypothyroidism versus 34% in patients without hypothyroidism. In the univariate model, the odds ratio (OR) for patients who had new onset hypothyroidism was 2.0 (95% CI: 1.0, 3.7; P=0.038), suggesting they were 2 times more likely to have a clinical benefit than were patients without hypothyroidism. We grouped tumor types into two classes (good risk (breast, gyn, CRC, lung, H/N, GU, Biliary, HCC: 53/114= 46% clinical benefit) and poor risk (melanoma, pancreas, upper GI, others: 24/84= 29% clinical benefit)) based on the proportion of patients experiencing clinical benefit. When adjusted for tumor class, age (>50 years old), sex, the OR was 2.6 (95% CI: 1.3, 5.3; P=0.007) (Table). Conclusions: New onset hypothyroidism is a positive prognostic indicator for favorable clinical benefit in patients who received TKI treatment. TableVariableContrastOR (95% CI)*p-valueHypothyroidYes vs. No2.6 (1.3, 5.3)0.007SexMale vs. Female0.8 (0.4, 1.6)0.58Age>50 vs. ≤501.5 (0.7, 3.0)0.3Tumor ClassPoor vs. Good0.4 (0.2, 0.7)0.004*OR > 1 indicates factor increases probability of clinical benefit Citation Format: Mehmet Asim Bilen, Amy Patel, Kenneth R. Hess, Javier Munoz, Naifa Busaidy, Maen Abdelrahim, Jennifer Wheler, Filip Janku, Gerald S. Falchook, David S. Hong, Funda Meric-Bernstam, Mohammed A. Habra, Aung Naing. Association between new onset hypothyroidism and clinical response in patients treated with tyrosine kinase inhibitor (TKI) therapy in phase I clinical trials. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2827. doi:10.1158/1538-7445.AM2014-2827