Signal Transduction Events and the Regulation of Cell Growth

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In FY2023, our main activities were working with clinical investigators to develop new pharmacodynamic (PD) assays tailored to their clinical trials and implementing these PD assays in the trials open during the same period. Our specific objectives include: 1. Determining if a therapy hit its target in the patient. 2. Investigating the impact of the therapy on the host, both at the systemic level, and in the tumor and tumor microenvironment. 3. Introducing new technology, including transfer of our technology intramurally and extramurally. 4. Identifying new drug targets and mechanisms. Throughout FY2023, we collaborated on over 60 clinical trials. Our focus in biomarker analysis was primarily on three main areas: 1. Immune PD. 2. Rare cell non-immune PD (e.g., circulating tumor cells and circulating cancer associated fibroblasts). 3. Analyses of gene expression, applicable to fresh, frozen, or formalin-fixed, paraffin-embedded tissue (FFPE). Furthermore, we investigated the 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 and published correlations with survival in multiple clinical trials. These exploratory data have provided insights into the impact of therapy on peripheral immunity. Additionally, these data serve as a potential blood-based indicator of response to checkpoint blockade, as demonstrated in our 2019 publication in collaboration with a clinical team led by Drs. Karzai, Madan, Gulley, and Dahut, studying immune profiling of castration-resistant prostate cancer patients treated with the anti-PD-L1 antibody durvalumab in combination with the PARP inhibitor olaparib, revealing evidence of CD8+ T cell reinvigoration. Regarding immune phenotyping studies, we focused on multiple populations and subpopulations, including monocytes, tumor-associated macrophages, myeloid-derived suppressor cells, activated and regulatory T-cells, and the expression of functional markers. In 2023 we completed immune profiling of triple-negative breast cancer patients treated with durvalumab plus olaparib. This study was done in collaboration with Dr. Jung-Min Lee and a manuscript is in preparation for publication. Additionally, we collaborated with Dr. Brigitte Widemann and her team on immune analysis of peripheral blood in neurofibromatosis type 1 (NF1) patients and patients with inoperable plexiform neurofibromas treated with selumetinib. In another trial with Dr. Widemann, we analyzed immune subsets in patients with unresectable or metastatic malignant peripheral nerve sheath tumors treated with selumetinib in combination with sirolimus. During the FY2022 to 2023 period, in collaboration with Dr. Andrea Apolo, we continued to define the impact of cabozantinib on systemic immunity in combination with the checkpoint inhibitors nivolumab and ipilimumab. In FY2023, we also continued our collaborations with Dr. Anish Thomas on immune profiling and circulating tumor cell analyses of small cell lung cancer (SCLC) clinical trials. This includes the publication of our circulating tumor cell results by Dr. Thomas in Cancer Cell in 2022. In addition, we analyzed immune subsets in the patients with SCLC, extra-pulmonary small cell neuroendocrine cancer, or homologous recombination-deficient cancers resistant to PARP inhibitors, who were treated with sacituzumab govitecan plus berzosertib. Additionally, in collaboration with Dr. Nitin Roper, we investigated immune subset changes in the tumor of SCLC mice with and without Notch activating drug. For circulating tumor cells, we have been utilizing our own magnetic bead enrichment method for CTC enumeration and phenotypic characterizations. To further advance CTC characterization we have been exploring methods to enrich and isolate CTCs. Currently, we are testing two instruments and a method utilizing magnetic beads and columns. In collaboration with Dr. Anish Thomas, we initiated this effort in SCLC patient samples to characterize them at a multicellular level and single-cell level. We have started three trials in FY23 to assess digital spatial gene expression profiling in FFPE samples in peritoneal carcinomatosis, adrenocortical carcinoma, and pancreatic cancer.