Browsing by Author "Zamarin, Dmitriy"

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    A Phase 2 Study of Dasatinib in Recurrent Clear Cell Carcinoma of the Ovary, Fallopian Tube, Peritoneum or Endometrium: NRG Oncology/Gynecologic Oncology Group Study 0283
    (Elsevier, 2023) O’Cearbhaill, Roisin E.; Miller, Austin; Soslow, Robert A.; Lankes, Heather A.; DeLair, Deborah; Segura, Sheila; Chavan, Shweta; Zamarin, Dmitriy; DeBernardo, Robert; Moore, Kathleen; Moroney, John; Shahin, Mark; Thaker, Premal H.; Wahner-Hendrickson, Andrea E.; Aghajanian, Carol; Pathology and Laboratory Medicine, School of Medicine
    Objective: Gynecologic cancers are traditionally managed according to their presumed site of origin, without regard to the underlying histologic subtype. Clear cell histology is associated with chemotherapy refractoriness and poor survival. Mutations in SWI/SNF chromatin remodeling complex member ARID1A, which encodes for BAF250a protein, are common in clear cell and endometriosis-associated endometrioid carcinomas. High-throughput cell-based drug screening predicted activity of dasatinib, a tyrosine kinase inhibitor, in ARID1A-mutant clear cell carcinoma. Methods: We conducted a phase 2 clinical trial of dasatinib 140 mg once daily by mouth in patients with recurrent or persistent ovarian and endometrial clear cell carcinoma. Patients with measurable disease were enrolled and then assigned to biomarker-defined populations based on BAF250a immunohistochemistry. The translational endpoints included broad next-generation sequencing to assess concordance of protein expression and treatment outcomes. Results: Twenty-eight patients, 15 of whom had tumors with retained BAF250a and 13 with loss of BAF250a were evaluable for treatment response and safety. The most common grade 3 adverse events were anemia, fatigue, dyspnea, hyponatremia, pleural effusion, and vomiting. One patient had a partial response, eight (28%) had stable disease, and 15 (53.6%) had disease progression. Twenty-three patients had next-generation sequencing results; 13 had a pathogenic ARID1A alteration. PIK3CA mutations were more prevalent in ARID1A-mutant tumors, while TP53 mutations were more prevalent in ARID1A wild-type tumors. Conclusions: Dasatinib was not an effective single-agent treatment for recurrent or persistent ovarian and endometrial clear cell carcinoma. Studies are urgently needed for this rare gynecologic subtype.
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    Cancer associated fibroblasts serve as an ovarian cancer stem cell niche through noncanonical Wnt5a signaling
    (Springer Nature, 2024-01-08) Fang, Yiming; Xiao, Xue; Wang, Ji; Dasari, Subramanyam; Pepin, David; Nephew, Kenneth P.; Zamarin, Dmitriy; Mitra, Anirban K.; Medicine, School of Medicine
    Frequent relapse and chemoresistance cause poor outcome in ovarian cancer (OC) and cancer stem cells (CSCs) are important contributors. While most studies focus exclusively on CSCs, the role of the microenvironment in providing optimal conditions to maintain their tumor-initiating potential remains poorly understood. Cancer associated fibroblasts (CAFs) are a major constituent of the OC tumor microenvironment and we show that CAFs and CSCs are enriched following chemotherapy in patient tumors. CAFs significantly increase OC cell resistance to carboplatin. Using heterotypic CAF-OC cocultures and in vivo limiting dilution assay, we confirm that the CAFs act by enriching the CSC population. CAFs increase the symmetric division of CSCs as well as the dedifferentiation of bulk OC cells into CSCs. The effect of CAFs is limited to OC cells in their immediate neighborhood, which can be prevented by inhibiting Wnt. Analysis of single cell RNA-seq data from OC patients reveal Wnt5a as the highest expressed Wnt in CAFs and that certain subpopulations of CAFs express higher levels of Wnt5a. Our findings demonstrate that Wnt5a from CAFs activate a noncanonical Wnt signaling pathway involving the ROR2/PKC/CREB1 axis in the neighboring CSCs. While canonical Wnt signaling is found to be predominant in interactions between cancer cells in patients, non-canonical Wnt pathway is activated by the CAF-OC crosstalk. Treatment with a Wnt5a inhibitor sensitizes tumors to carboplatin in vivo. Together, our results demonstrate a novel mechanism of CSC maintenance by signals from the microenvironmental CAFs, which can be targeted to treat OC chemoresistance and relapse.