ZIC SC 006743 (ZIC) | |||
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Title | Signal Transduction Events and the Regulation of Cell Growth | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Trepel, Jane | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $553,334 | Project Dates | null - null |
Fiscal Year | 2018 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) Chemotherapy (30.0%) Interferon (1.0%) Metastasis (40.0%) Neurofibromatosis (8.0%) Childhood Cancers (15.0%) |
Bladder (10.0%) Brain (1.0%) Breast (11.0%) Esophagus (4.0%) Head and Neck (2.0%) Kidney Disease (2.0%) Larynx (1.0%) Lung (30.0%) Nervous System (9.0%) Non Hodgkins Lymphoma (2.0%) Ovarian Cancer (10.0%) Prostate (28.0%) Urinary System (12.0%) Kidney Cancer (2.0%) |
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Research Type | |||
Technology Development and/or Marker Discovery Systemic Therapies - Discovery and Development |
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Abstract | |||
Our major activities in FY2018 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 FY2018. 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 40 clinical trials in FY2018. 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 (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 response, progression-free survival and overall survival in multiple clinical trials in FY2018. 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 early predictor of response to PD-1 blockade. In a collaboration this year with a clinical team including Drs. Karzai, Madan, Gulley, Lee and Dahut on immune profiling of castration-resistant prostate cancer patients treated with the anti-PD-L1 antibody durvalumab plus the PARP inhibitor olaparib we demonstrated 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. 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. This is particularly important as it is increasingly recognized that immunotherapy may be used in combination with other immune-directed therapies, with or without other classes of drug, i.e. cytotoxic, epigenetic, kinase inhibitors, etc. or as a component of multimodality therapy protocols. 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 in FY2018. In 2017 we published the first immune profiling of the systemic response to an HDAC inhibitor in clinical trial and in FY2018, we are performing immune subset analysis on multiple HDAC inhibitor clinical trials, including combination therapy trials with checkpoint inhibitors. In a translational study with Dr. Pommier, we contributed to the discovery that class I-selective HDAC inhibitors induce expression of SLFN11, overcoming resistance to DNA-targeted agents. Working on chaperone inhibitors we previously identified Hsp40 as a new anticancer target. NIH filed for patent on this invention and the patent issue in FY2018. We have been collaborating with Dr. Widemann and her team, on analysis of the immune infiltrate in NF |