Cara Statz

mTOR Inhibitors in Castration-Resistant Prostate Cancer: A Systematic Review

AbstractBackgroundThe progression of prostate cancer to castration-resistant prostate cancer (CRPC) is often a result of somatic alterations in the PI3K/Akt/mTOR (mammalian target of rapamycin) pathway, suggesting that therapies targeting this pathway might lead to improved survival and efficacy. Here, we systematically evaluate the results of clinical trials investigating mTOR inhibition in CRPC and utilize preclinical data to predict clinical outcomes.MethodsTrials included in the study were identified through PubMed and via review of conference abstracts cited by relevant review articles. The eligibility of trials was independent of sample size, clinical setting, or date.ResultsA total of 14 studies were eligible for qualitative analysis. The clinical setting was variable among studies, and all utilized an allosteric mTOR inhibitor as either a monotherapy or in combination. Molecular criteria were evaluated in three trials. Among most studies, the prostate-specific antigen level declined during treatment, but often increased shortly thereafter. Partial responses to treatment were minimal, and no complete responses were reported. Two studies exploring therapy with an mTOR inhibitor in combination with bicalutamide resulted in minimal efficacy. Overall, allosteric mTOR inhibition was deemed to be inadequate for the treatment of CRPC.ConclusionPreclinical data suggest that a reciprocal feedback mechanism between PI3K and androgen receptor signaling is a potential mechanism behind the clinical inefficacy of mTOR inhibitors in CRPC, indicating combinatorial targeting of PI3K, mTORC1/2, and the androgen receptor might be more effective. Comprehensive analysis of preclinical data to assess clinical trial targets and efficacy may reduce the number of unproductive trials and identify potentially beneficial combinatorial therapies for resistant disease.

Barriers preventing the adoption of comprehensive cancer genomic profiling in the clinic

ABSTRACT Introduction: Comprehensive cancer genomic profiling provides the opportunity to expose the various molecular aberrations potentially driving tumor progression. Consequently, the identity of these genetic drivers can be utilized to match a patient to the most appropriate targeted therapy, thereby increasing the probability of improved clinical outcome. Despite its capability of informing patient care, the adoption of comprehensive cancer genomic profiling in the clinic has not been widespread. The barriers surrounding its universal acceptance are attributed to both physician and patient perspectives. Areas covered: The following report discusses the various obstacles in place, including those related to clinical utility, education, insurance coverage, and clinical trials, which can deter physicians and patients from utilizing genomic profiling for therapeutic decision-making. Expert commentary: The authors review the recent growth and potential of clinical utility studies over the last two years, provide a suggestive framework for educational support, and comment on the use of social media to enhance clinical trial recruitment.

Abstract 541: A comprehensive analysis delineating the immunotherapeutic terrain of cancer-related clinical trials

Technological innovations have facilitated a greater understanding of how the tumor microenvironment contributes to cancer, leading to rapid FDA approval of four immunotherapies. To assess how these therapies are being further investigated in combination with other therapies and in tumor types outside of the current FDA approval, we performed a comprehensive analysis of the curated clinical trials in the JAX Clinical Knowledgebase (JAX-CKB). In brief, clinical trials investigating Atezolizumab, Nivolumab, Pembrolizumab, and Ipilimumab, curated from clinicaltrials.gov, were queried in the JAX-CKB and then analyzed for comparison. Further analyses were executed to illustrate possible unmet needs within the field of cancer therapeutics. Of the four immunotherapies, Pembrolizumab was identified with the greatest number of clinical trials overall, with 305 compared to Atezolizumab, 79, Nivolumab, 183, and Ipilimumab, 126. Of these trials the number of trials investigating Pembrolizumab, Atezolizumab, Nivolumab, or Ipilimumab in combination with another therapy was higher than those investigating one of the four immunotherapies as a monotherapy. Phase II trials for both single therapy and combinatorial therapies were greater than both Phase I and Phase III for the same groups, regardless of therapy. On average, 12% ± 3.8% of the combined trials for all four drugs included any advanced solid tumor. Nivolumab combined with Ipilimumab demonstrated the greatest number of trials (61) investigating an immunotherapy in combination with another immunotherapy. Among those, 30 were Phase II trials, 16 were Phase I, and 14 were Phase III. Across five cancer indications (lung, pancreatic, ovarian, prostate, and colon), lung cancer was most commonly indicated in the trials, among all four drugs. Prostate was indicated in the least number of trials, with Ipilimumab ranking the highest (10). The recent success with immunotherapies has garnered significant interest in understanding how these therapies will perform in different tumor types and whether specific combinations will have a greater impact. Interrogation of the clinical trial terrain in the JAX-CKB provides a basis for determining additional investigations that might be warranted. Citation Format: Cara M. Statz, Sara E. Patterson, Taofei Yin, Susan M. Mockus. A comprehensive analysis delineating the immunotherapeutic terrain of cancer-related clinical trials [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 541. doi:10.1158/1538-7445.AM2017-541

Abstract 3630: Validation of the Archer FusionPlex solid tumor panel in the JAX cancer treatment profileTM

Introduction: A comprehensive somatic tumor profile with associated treatment selection options requires the detection of gene fusions. After evaluating the clinical utility of multiple methods of gene fusion detection, it was determined that the Archer FusionPlex Solid Tumor Panel (AFPSTP) best compliments the JAX Cancer Treatment Profile TM (JAX-CTP TM ) clinical test in terms of workflow, specimen requirements and turnaround time. Here we describe our analytical validation process for the AFPSTP assay. Methods: AFPSTP was validated using 24 samples: 5 JAX Patient Derived Xenograft (PDX) cases, 4 translocation positive controls, 2 FFPE cancer samples, 1 normal tissue sample, and 12 cell lines. Nine of the cell lines were previously identified as positive for fusion transcripts and 3 lacked detectable fusion events. The validation was executed in 5 phases: (1) confirm that AFPSTP was able to detect known fusion or lack of fusion events in characterized specimens; (2) determine inter-assay concordance; (3) determine intra-assay concordance; (4) LOD and (5) sensitivity. Results: The fusion detection results for this validation are listed in Table 1. All but one of these fusion events was previously identified. The one novel fusion was confirmed using TaqMan RT-PCR. In addition to the expected fusions, 4 false positive events were detected, 2 due to mispriming and 2 determined to be WT read through transcripts. The fusion detection inter and intra-assay concordance was found to be 100% and the sensitivity was calculated to be 91.67% at a LOD of 5%. Conclusion: This analysis outlines the clinical validation of the incorporation of AFPSTP into the JAX-CTP TM test system. Once incorporated, the AFPSTP assay will accomplish the goal of making JAX-CTP TM a more comprehensive somatic tumor profiling assay without affecting the current acceptable turnaround time or required input material. Citation Format: Samantha Helm, Aleksandra Ras, Vanessa Spotlow, Kevin Kelly, Susan Mockus, Cara Statz, Guruprasad Ananda, Joan Malcolm, Gregory J. Tsongalis. Validation of the Archer FusionPlex solid tumor panel in the JAX cancer treatment profile TM . [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3630.