Utilizing Glycosaminoglycans as a Theragnostic Approach for Treating Platinum-Resistant Gynecological Malignancies

. Project Summary. Ovarian cancer (OC) is usually diagnosed at advanced stages, and platinum-based chemotherapy with surgical debulking remains the most effective first line treatment for all OC subtypes. Although the initial response rate is high, most patients develop drug-resistant terminal cancer relapse within 5 years. Overcoming the mechanisms contributing to platinum resistance is urgently needed for improvingbthe treatment outcomes. Sulfated glycosaminoglycans (GAG), such as heparan sulfate (HS) and chondroitinbsulfate (CS), are linear polymers of repeated disaccharide units that are modified by addition of sulfate groups. High levels of GAG and high expression of proteoglycans (proteins with attached GAG) at the cell surface and within the extracellular matrix can promote cancer progression and chemoresistance, thus positioning GAG as emerging relevant factor in the treatment of OC. Previously, we discovered that GAG mediate the tumor uptake of Triplatin, a positively charged trinuclear platinum (Pt) agent of a structurally distinct class from the mononuclear Pt drugs. The efficacy of Pt drugs depends on the tumor uptake, and drug tumor accumulation is essential for increasing the potency and diminishing toxic side effects. A central HYPOTHESIS of our Translational Exploratory/Developmental study is that high expression of C4S contributes to platinum resistance in OC, which can be overcome by GAG-targeted drugs, such as Triplatin. Clear cell ovarian carcinoma tumors are known to portend a worse prognosis than high grade serous or endometrioid OC, in part due to inherent resistance to platinum-based chemotherapy and lack of novel therapies for these high-risk histologic subtypes. The overarching goal of this study is the elimination of mortality associated with Pt-resistant OC by improving drug tumor penetration, accumulation, and selectivity. This study can benefit the patient by using the GAG profiling to predict the response to the conventional or novel platinum drugs such as Triplatin. The proposal will be the first to use a mechanism-based approach for precision medicine of platinum anticancer agents. This study aims to refine and validate this approach for the future clinical translation. To validate our hypothesis and to advance the use of Triplatin against platinum-resistant OC subtypes, this study will use in vivo murine tumor models because they enable assessment of antitumor efficacy, intra-tumor and organ drug accumulation, as well as the platinum drug interaction with stromal, vascular, and immune context that cannot be recapitulated in vitro. Project will be deemed a success when 1) the role of GAGs in platinum resistance is established, 2) Triplatin shows significant improvement over the available therapies in treatment of Pt-resistant primary and recurrent OC and 3) a candidate diagnostic companion marker is characterized to identify what patients will benefit most. Success of this study would have a significant positive impact on survival outcomes for OC patients, their families and community. Project Number: 1R21CA308922-01 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Larisa Litovchick (+1 co-PI) | Institution: VIRGINIA COMMONWEALTH UNIVERSITY, RICHMOND, VA | Award Amount: $399,187 | Activity Code: R21 | Study Section: Special Emphasis Panel[ZRG1 CTH-X (56)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11285626