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Principal Investigator: JANE B TREPEL
Organization: DIVISION OF CLINICAL SCIENCES - NCI
Fiscal Year: 2020
Award: $1,097,545
Funding agency: National Cancer Institute
Our major activities in FY2020 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 FY2020. 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 FY2020. 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 examine 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 in FY2020. 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.) in 2017, 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. and in FY2020, we have performed immune subset analysis on multiple HDAC inhibitor clinical trials, including combination therapy trials with checkpoint inhibitors. 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 and chaperone inhibitors. 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 9 published clinical trials, two currently submitted manuscripts and one manuscript in preparation. In 2017 we published the first immune profiling of the systemic immune response to an HDAC inhibitor in clinical trial. In FY2020 we published the induction of hyperacetylation in pediatric patients in response to combination epigenetic therapy in collaboration with Dr. Patrick Brown, Johns Hopkins University (Clin. Cancer Res.). We have a manuscript submitted on the first pediatric trial of the HDAC inhibitor entinostat in collaboration with the Pediatric Early Phase Clinical Trials Network, which includes specialists in pediatric oncology from some of the premier research institutions in the United States. We also have a manuscript in preparation on a clinical trial of entinostat plus pembrolizumab in metastatic non-small cell lung cancer. 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 has recently finished accrual and we completed our PD assessment. We are helping to bring entinostat to Japan for the treatment of women with breast cancer. Working closely with Kyowa Kirin, we completed the Phase I clinical trial of entinostat as monotherapy or in combination with exemestane and this study has been submitted for publication. In FY2020 working with Kyowa Kirin we completed a Phase 2 study of the same design. Overall, we are 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, Broad Institute), 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 patent issued in FY2018. 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 2020, 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 FY2020 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, with several manuscripts currently under review. We have a new collaboration with Dr. Nitin Roper on SCLC with a manuscript under review. We have continued our collaborations with Dr. Jay Berzofsky and his team on circulating tumor cells and immune subsets in breast cancer and prostate cancer patients treated with vaccine therapy, with a manuscript currently in preparation. We have continued our collaborations with Drs. Madan, Karzai, Gulley and Dahut on prostate cancer pharmacodynamics, and have several manuscripts in preparation or under review. 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's 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). We 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 (Clin. Cancer Res. 2020).
Terms: <ACRIN><Academia><American College of Radiology Imaging Network><Antibodies><Anzatax><Apoptotic><Area><Aromasin><Aromasine><Asotax><Assay><Award><Bioassay><Biologic Assays><Biological><Biological Assay><Biological Markers><Biotech><Biotechnology><Blood><Blood Reticuloendothelial System><Blood monocyte><Breast Cancer><Bristaxol><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CHEK1><CHEK1 gene><CHK1><Cancer Patient><Cancers><Capillary Leak Syndrome><Cell Body><Cell Communication and Signaling><Cell Signaling><Cell-Cycle Checkpoint Kinase><Cells><Cellular Regulation><Chaperone><Characteristics><Checkpoint inhibitor><Checkpoint kinase 1><Childhood><Clinic><Clinical><Clinical Drug Development><Clinical Drug Testing/Development><Clinical Investigator><Clinical Research><Clinical Study><Clinical Trials><Clinical Trials Network><Collaborations><Combined Modality Therapy><DNA-6-O-Methylguanine[protein]-L-Cysteine S-Methyltransferase><Data><Drug Design><Drug Targeting><Drugs><EC 2.1.1.63><ECOG><EXTMR><Early-Stage Clinical Trials><Eastern Cooperative Oncology Group><Elephantiasis Neuromatosis><Endothelial Cells><Event><Exemestane><Extramural><Extramural Activities><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Formalin><Freezing><Future><Gene Expression><Gene Expression Monitoring><Gene Expression Pattern Analysis><Gene Expression Profiling><Glial Cell Tumors><Glial Neoplasm><Glial Tumor><Glioblastoma><Glioma><Goals><Grade IV Astrocytic Neoplasm><Grade IV Astrocytic Tumor><Grade IV Astrocytoma><Guanine-O(6)-Alkyltransferase><HDAC Agent><HDAC inhibitor><Histone Deacetylase Inhibitor><Histone deacetylase inhibition><Immune><Immune checkpoint inhibitor><Immune infiltrates><Immune response><Immunes><Immunity><Immunologic Subtyping><Immunological response><Immunophenotyping><Innate Immunity><Institutes><Institution><Intermediary Metabolism><International><Intracellular Communication and Signaling><Japan><Laboratories><Legal patent><MGMT><MGMT gene><Malignant Neoplasms><Malignant Ovarian Neoplasm><Malignant Ovarian Tumor><Malignant Peripheral Nerve Sheath Tumor><Malignant Schwannoma><Malignant Tumor><Malignant Tumor of the Ovary><Malignant Tumor of the Prostate><Malignant neoplasm of ovary><Malignant neoplasm of prostate><Malignant prostatic tumor><Manuscripts><Marrow monocyte><Medication><Metabolic><Metabolic Processes><Metabolism><Methylated-DNA Protein-Cysteine Methyltransferase><Methylated-DNA-Protein-Cysteine S-Methyltransferase><Methylguanine-DNA Methyltransferase Gene><Molecular><Molecular Chaperones><Molecular Target><Multimodal Therapy><Multimodal Treatment><Mutate><Myeloid-derived suppressor cells><NF-1><NF-1 Protein><NF-1 encoded protein><NF1><NF1 GRP><NF1 Protein><NF1 gene><NF1-GAP-Related Protein><NIH><NSCLC><NSCLC - Non-Small Cell Lung Cancer><National Institutes of Health><Native Immunity><Natural Immunity><Nature><Neoplasm Circulating Cells><Neoplasms><Neurofibromatosis 1 Genes><Neurofibromatosis Type 1 Gene Product><Neurofibromatosis Type 1 Protein><Neurofibromin><Neurofibromin 1><Neurofibrosarcoma><Neurogenic Sarcoma><Neuroglial Neoplasm><Neuroglial Tumor><Non-Small Cell Lung Cancer><Non-Small-Cell Lung Carcinoma><Non-Specific Immunity><Non-metastatic><Nonmetastatic><Nonsmall Cell Lung Carcinoma><Nonspecific Immunity><O(6)-AGT><O(6)-Alkylguanine-DNA Alkyltransferase><O(6)-MeG-DNA Methyltransferase><O(6)-Methylguanine DNA Transmethylase><O(6)-Methylguanine Methyltransferase><O(6)-Methylguanine-DNA Methyltransferase><O6-Alkylguanine DNA Alkyltransferase><Oat cell carcinoma><Oncologist><Ovary Cancer><Pachydermatocele><Paclitaxel><Paclitaxel (Taxol)><Pancreas Adenocarcinoma><Pancreatic Adenocarcinoma><Paraffin Embedding><Patents><Patients><Pediatric Oncology><Peripheral><Pharmaceutic Preparations><Pharmaceutical Preparations><Pharmacodynamics><Phase><Phase 1 Clinical Trials><Phase I Clinical Trials><Plexiform Neurofibroma><Plexiform Neuromas><Population><Praxel><Preparation><Process><Prostate CA><Prostate Cancer><Prostatic Cancer><Publications><Publishing><Research><S Period><S Phase><Sampling><Scientific Publication><Serous><Severities><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Small Cell Lung Cancer><Specialist><Synthesis Period><Synthesis Phase><Systemic Capillary Leak Syndrome><T cell infiltration><T cell tumor trafficking><T-Cells><T-Lymphocyte><T8 Cells><T8 Lymphocytes><TNBC><Taxol><Taxol A><Taxol Konzentrat><Technology><Therapy trial><Tissue Embedding><Transcript Expression Analyses><Transcript Expression Analysis><Transitional Carcinoma><Transitional Cell Carcinoma><Translational Research><Translational Science><Tumor Royale><Tumor-associated macrophages><Tumor-infiltrating immune cells><United States><United States National Institutes of Health><Universities><Urothelial Carcinoma><VAC-TX><Vaccine Therapy><Woman><Work><adaptive immunity><advanced breast cancer><advanced stage breast cancer><alkylguanine DNA alkyltransferase><anti-cancer><anti-cancer research><anticancer><anticancer research><base><bio-markers><biologic marker><biological signal transduction><biomarker><cancer clinical trial><cancer microenvironment><cancer research><castrate resistant PCa><castrate resistant prostate cancer><castration resistant PCa><castration resistant prostate cancer><cell growth regulation><cell-cycle check point kinase><check point blockade><check point kinase 1><checkpoint blockade><child patients><chk1 kinase><chk1 protein kinase><circulating neoplastic cell><circulating tumor cell><clinical biomarkers><clinical development><clinically useful biomarkers><combination therapy><combined modality treatment><combined treatment><design><designing><digital><drug development><drug discovery><drug mechanism><drug/agent><early clinical trial><early phase clinical trial><effector T cell><epigenetic therapy><expression subtypes><flow cytophotometry><gene expression analysis><gene expression assay><glial-derived tumor><glioblastoma multiforme><hormone receptor-positive><host response><immune cell infiltrate><immune check point blockade><immune check point inhibitor><immune checkpoint blockade><immune infiltration><immunophenotype><immunoresponse><immunosuppressive myeloid cells><in vivo><inhibitor><inhibitor/antagonist><insight><intratumoral immune cell><invention><lung oat cell carcinoma><lung small cell carcinoma><lung small cell neuroendocrine carcinoma><malignancy><malignant breast neoplasm><malignant breast tumor><methylguanine DNA methyltransferase><molecular sub-types><molecular subsets><molecular subtypes><monocyte><multi-modal therapy><multi-modal treatment><neoplasia><neoplasm/cancer><neoplastic growth><neuro-oncology><neurofibroma><neurofibromatosis type 1 gene><neurofibromatosis type 1 protein/gene><neuroglia neoplasm><neuroglia tumor><neurooncology><new drug target><new drug treatments><new druggable target><new drugs><new pharmacotherapy target><new technology><new therapeutic target><new therapeutics><new therapy><new therapy target><next generation therapeutics><nf 1 Genes><nonsmall cell lung cancer><novel><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmacotherapy target><novel technologies><novel therapeutic target><novel therapeutics><novel therapy><novel therapy target><oat cell cancer><oncology clinical trial><ovarian cancer><pediatric><pediatric patients><peripheral blood><phase 2 study><phase 2 trial><phase 3 trial><phase I protocol><phase II study><phase II trial><phase III trial><programs><response><response to treatment><small cell undifferentiated carcinoma><spongioblastoma multiforme><suppressive myeloid cells><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic agent development><therapeutic development><therapeutic response><therapeutic vaccination><thymus derived lymphocyte><transcriptional profiling><translation research><translational investigator><translational researcher><translational scientist><treatment response><trend><triple-negative breast cancer><triple-negative invasive breast carcinoma><tumor><tumor immune cell><tumor microenvironment>