Prostate cancer (PCa) remains a significant global health challenge, with rising morbidity rates and poor prognosis associated with advanced stages, particularly in cases complicated by cachexia—a severe wasting syndrome that drastically reduces patient survival and quality of life. The complexity of PCa progression necessitates the identification of new, targeted solutions beyond conventional treatments.
The newly published review focuses intensely on Growth Differentiation Factor 15 (GDF15), a distinct member of the Transforming Growth Factor-beta (TGF-β) superfamily. While GDF15's role in other cancers is varied, the review clarifies its significant, multifaceted involvement in PCa. Mechanistically, GDF15 is hypothesized to drive PCa progression and promote cachexia through its interactions with PCa lipid metabolism and stromal activation.
Furthermore, GDF15 plays a critical role in mediating PCa bone metastasis. For instance, it enhances the function of stromal cells (primarily osteoblasts), increasing the secretion of CCL2 and RANKL, which subsequently recruits osteoclasts and activates osteoclastogenesis, ultimately facilitating the growth of metastatic PCa within the bone microenvironment.
A major challenge in advanced PCa treatment is the development of chemoresistance, particularly to standard agents like docetaxel. The review emphasizes GDF15's impact in this area, suggesting it is a crucial player in drug responses. Studies have indicated that GDF15 acts as a cytoprotective mechanism in prostate carcinomas exposed to chemotherapy, directly contributing to resistance. Data from androgen-independent PCa cell lines show that GDF15 is upregulated in docetaxel-resistant cells, and its knockout restored docetaxel sensitivity in resistant cells. This highlights GDF15 as a promising target to resensitize tumors to existing chemotherapy agents, supporting the finding that GDF15 inhibition might be a potential therapeutic strategy for improving docetaxel efficacy.
The clinical utility of GDF15 extends to diagnosis, surveillance, and prognosis. While Prostate-Specific Antigen (PSA) is the current primary indicator, its lack of tumor specificity frequently leads to false positives. GDF15 offers a more nuanced approach. Serum GDF15 levels are lower in localized PCa but significantly higher in metastatic PCa compared to normal tissue.
Crucially, the review notes the synergistic power of combining GDF15 with established markers. An algorithm combining GDF15 and PSA, termed the MIC-PSA score, specifically enhances PCa diagnosis and can reduce unnecessary biopsies by 27% compared to using PSA alone. Furthermore, combining GDF15 with a panel of other markers has demonstrated superior performance in predicting aggressive low-risk PCa. Beyond serum, GDF15's potential as an independent predictor of poorer cancer-specific survival, and its ability to distinguish indolent from lethal localized PCa, establishes it as a valuable prognostic tool.
Perhaps the most exciting finding is the advancement of monoclonal antibodies targeting GDF15 in clinical trials. These antibodies aim to disrupt the GDF15-mediated signaling pathways that drive cachexia and chemoresistance. Key monoclonal antibodies in clinical development include: AV-380, an inhibitory antibody which has shown efficacy in reversing cachexia-related phenotypes, rehabilitating weight, muscle, and fat mass in preclinical models; NGM120, a novel GFRAL antagonist which targets the receptor for GDF15 and has demonstrated anti-cancer activity in advanced PCa patients in a Phase 1a trial, with one patient achieving a partial response; and Visugromab, which neutralizes GDF15 to improve the effectiveness of PD1/PDL1 immunotherapy by enhancing immune cell infiltration into the tumor microenvironment. Other promising candidates include Ponsegromab and AZD8853, which are also undergoing clinical evaluation for treating cancer-related cachexia and potentially overcoming immunotherapy resistance.
The review concludes that the complex interactions involving GDF15 offer numerous points for therapeutic intervention, marking GDF15 as an indispensable target in developing next-generation precision medicine approaches for prostate cancer patients.
