SAT-291 - Retrospective in Silico Analyses Identify GH as A Driver of Tumor Therapy Resistance and Immune Suppression and A Negative Prognostic Factor in Gynecologic Malignancies of Ovary, Cervix, Endometrium

Targeting the growth hormone receptor (GHR) has emerged as a promising antineoplastic strategy due to its role in driving tumor progression and therapy resistance, buttressed by highly consistent and large volume of pre-clinical and epidemiologic data over the last 70 years. Based on the above, we conducted a comprehensive retrospective in silico analyses into the sparsely studied area of clinical relevance of GHR signaling in gynecologic malignancies – cancers of cervix, ovary, and the endometrium. Publicly available transcriptomic data from The Cancer Genome Atlas (TCGA) from patient cohorts for ovarian (OV, 373 patients), cervical (CESC, 304 patients), and endometrial (UCEC, 542 patients) cancers were used for survival and gene-set enrichment analyses. Our findings reveal that GHR mRNA expression levels are significantly elevated in malignant tissues compared to adjacent normal controls across all three cancer types. Survival analysis using Kaplan-Meier estimates and Cox proportional hazards modeling demonstrated that high GHR expression serves as a robust negative prognostic indicator, correlating significantly with reduced overall and progression-free survival. Furthermore, gene set enrichment analysis (GSEA) identified a strong association between high GHR expression and molecular signatures of platinum-based chemoresistance and immune evasion. Specifically, GHR-high tumors exhibited increased expression of ATP-binding cassette (ABC) transporters and a suppressed immune microenvironment characterized by reduced CD8+ T-cell infiltration and upregulated checkpoint markers. We additionally identified a set of tumor-supportive genes which are regulated by GH and consistently overlap between all 3 gynecologic malignancies in the TCGA dataset and cross-validated it against additional GEO datasets. These results provide provocative indications that the GHR as a pivotal driver of oncogenic resilience and immune suppression in female reproductive cancers. This in turn provides a strong rationale for the clinical development of GHR antagonists to improve outcomes in these high-mortality malignancies.

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