Signal Transduction Events and the Regulation of Cell Growth

Division Of Clinical Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

Our major activities in FY2021 were to work with clinical investigators to develop new pharmacodynamic (PD) assays tailored to their clinical trials and to implement these PD assays in the clinical trials we have open in FY2021. Our specific objectives are (1) to determine if a therapy hit its target in the patient; (2) interrogate the impact of the therapy on the host, both at the systemic level, and in the tumor and tumor microenvironment; (3) work with clinical investigators to introduce new technology into their programs, including transfer of our technology intramurally, extramurally and internationally; and (4) work in collaboration with clinical and basic translational investigators to identify new drug targets and new drug mechanisms. We worked on more than 60 clinical trials in FY2021. We have focused on three main areas of biomarker analysis; (1) immune PD, (2) rare cell non-immune PD (i.e. circulating tumor cells and circulating endothelial cells), and (3) digital analyses of gene expression that can be performed on fresh, frozen, or formalin-fixed, paraffin-embedded tissue, to greatly facilitate the assessment of gene expression in tumor samples. In addition, we examined systemic effects of immune- and non-immune targeted therapy on immune gene expression in peripheral blood. For the majority of the clinical trials on which we collaborate we are including immune PD as assessed by multiparameter flow cytometry. We have found correlations with survival in multiple clinical trials. These exploratory data have provided insight into the impact of therapy on peripheral immunity, which, as published in Nature (Wherry et al.) and PNAS (Ramalingam et al.), can provide valuable information reflective of the interaction of effector T cells and tumor and serve as a potential blood-based indicator of response to checkpoint blockade, as we published in 2019 in a collaboration with a clinical team including Drs. Karzai, Madan, Gulley and Dahut on immune profiling of castration-resistant prostate cancer patients treated with the anti-PD-L1 antibody durvalumab plus the PARP inhibitor olaparib demonstrating evidence of CD8+ T cell reinvigoration. We have also focused on multiple populations and subpopulations of monocytes, tumor-associated macrophages and myeloid-derived suppressor cells, including, as with T-cells, expression of functional markers. In FY2021, we have performed immune subset analysis on multiple HDAC inhibitor clinical trials. Together these data have afforded us a view of the functional interplay of innate and adaptive immunity in patients at baseline and in response to treatment, which in turn, suggests combination therapies for future clinical studies to enhance antitumor activity. Among drug classes we have focused on HDAC inhibitors, chaperone inhibitors, and the multikinase inhibitor cabozantinib. Previously we developed a PD assay for assessment of HDAC inhibitor activity in vivo. The NCI applied for a patent on our work, which issued in 2016. We have implemented this technology in multiple clinical trials, including 13 published clinical trials. In 2021 we published the first pediatric trial of the HDAC inhibitor entinostat in collaboration with the Pediatric Early Phase Clinical Trials Network (PMID: 33438318). We also published a manuscript on the impact of entinostat plus pembrolizumab on peripheral immunity in metastatic non-small cell lung cancer (PMID: 33203644). We are the National Laboratory Center of a Phase 3 ECOG-ACRIN Cancer Research Group FDA registration trial for entinostat in hormone receptor-positive advanced breast cancer, for which our PD is the only integrated biomarker. The trial was recently published and our PD assessment confirmed target inhibition in entinostat-treated patients (PMID: 34357781). We are helping to bring entinostat to Japan for the treatment of women with breast cancer. Working closely with Kyowa Kirin, we completed clinical trials of entinostat as monotherapy or in combination with exemestane and these studies have been submitted for publication. Overall, we have been working on clinical trials with 15 Branches of the NIH, three biotech companies and on two pharma trials with AstraZeneca, as well as four trials with academia (Johns Hopkins, Cleveland Clinic, Dana Farber, MIT), together encompassing Phase 1, Phase 2, and Phase 3 trials, both nationally and internationally. Working on chaperone inhibitors we previously identified Hsp40 as a new anticancer target. NIH filed for patent on this invention and the initial patent issued in FY2018 and a second patent issued in 2020. With Drs. Len Neckers of NCI and Jason Gestwicki of UCSF we are working on two DOD awards that include further development of drugs designed to hit the target we identified in my lab. We have been collaborating with Dr. Brigitte Widemann and her team on analysis of the immune infiltrate in NF1-associated tumors, including in 2021, immune analysis of peripheral blood and tumor of NF1-associated plexiform neurofibromas, atypical neurofibromas, atypical neurofibromatous neoplasms of uncertain biologic potential, and malignant peripheral nerve sheath tumors. In FY2021 we have continued our collaborations with Dr. Anish Thomas on immune profiling and circulating tumor cell analyses of his small cell lung cancer (SCLC) clinical trials, and published several manuscripts with with Dr. Thomas and Dr. Nitin Roper on SCLC (PMID: 34162872; PMID: 33848478). In FY21 we have continued our collaborations with Drs. Madan, Karzai, Gulley and Dahut on prostate cancer pharmacodynamics, and have several manuscripts in preparation, and a manuscript published in 2021 on cabozantinib plus docetaxel and prednisone in metastatic castration-resistant prostate cancer (PMID: 32969563). We performed PD analysis in Dr. Jung-min Lee's clinical trials of the CHK1 inhibitor prexasertib in BRCA wild-type triple-negative breast cancer (Oncologist, 2020), and BRCA wild-type high-grade serous ovarian cancer (J. Immunother. Cancer, 2020), and an analysis comparing innate and adaptive immune cells in the early course of patients with BRCA wild-type and mutated ovarian cancer (Oncol. Lett. 2019). We have performed immunophenotyping analysis in Dr. Neckers' study demonstrating the first in vivo activity of an LDH inhibitor (Cell Rep. 2020), and gene expression analysis of metabolism in Dr. Mioara Larion's analysis of metabolic reprogramming in molecular subtypes of IDH1mut gliomas (Neuro-oncology 2020). We developed an assay for MGMT gene expression from frozen and FFPE patient samples and contributed to Dr. Jing Wu's overview of MGMT status as a clinical biomarker in glioblastoma (Trends Cancer 2020). We identified the impact of cabozantinib on innate and adaptive immune cells in Dr. Andrea Apolo's Phase 2 trial of cabozantinib in metastatic urothelial carcinoma (Lancet Oncol. 2020). In FY2021 in collaboration with Dr. Apolo we have continued to define the the impact of cabozantinib on systemic immunity in combination with the checkpoint inhibitors nivolumab and ipilimumab (PMID: 32915679), and further analyses have been submitted and are in preparation. We have continued our work on circulating endothelial cells and identified an association of the severity of capillary leak syndrome with increases in apoptotic circulating endothelial cells in Dr. Christine Alewine's LMB-100 plus Nab-Paclitaxel trial of patients with advanced pancreatic adenocarcinoma (PMID: 31792036).