SUMMARY
The research of Viji Shridhar, Ph.D., focuses on understanding alterations in biological pathways and therapeutic vulnerabilities for treatment-refractory cancer. The aims of this research program are to align experimental compounds with optimal tumor selection and drug combinations to advance potential cancer treatments. This research also seeks to address corresponding vulnerabilities in in vitro and mouse models at the preclinical level.
Despite advances in treatment, ovarian cancer remains the most lethal gynecological malignancy, with a mortality of approximately 70%. High-grade serous ovarian cancer — the most common and deadliest type of ovarian cancer — initially responds to platinum-containing chemotherapy. But it acquires platinum resistance during therapy. Once platinum resistance occurs, as it does in all women who die from ovarian cancer, the median survival is one year. This highlights the urgent need for improved therapy.
Inhibitors of poly (ADP-ribose) polymerases improve relapse-free survival but not overall survival when administered as maintenance to women whose ovarian cancer has responded to adjuvant or neoadjuvant platinum therapy. Thus, there also is a need to improve the response to PARP inhibitors.
Dr. Shridhar is interested in two major biological pathways altered in cancer: growth factor signaling pathways and DNA damage response pathways. Current studies focus on testing novel drugs and repurposing drugs alone and in combination with PARP inhibitors.
Techniques commonly used in the lab include cell culture, real-time polymerase chain reaction, Western blotting, DNA methylation analysis, generation of gene constructs, cell transfection, immunofluorescence, immunohistochemistry and in vivo tumorigenic models.
Focus areas
- Repurposing clofarabine in combination with PARP inhibitors for treatment-resistant cancer. In Dr. Shridhar's continuous endeavors to identify innovative therapeutic combinations, she has made a recent discovery to treat patients with ovarian cancer. By using clofarabine (CLF) — a nucleoside analog similar to gemcitabine — to induce the nuclear localization of lysosomal protease cathepsin L (nCTSL), Dr. Shridhar observed an enhanced DNA damage response and increased sensitivity to the PARP inhibitor olaparib specifically and not other PARP inhibitors. Dr. Shridhar has uncovered a novel concept of inducing nuclear localization of CTSL with the CLF+ olaparib combination to induce DNA damage response, apoptosis and synergy with olaparib in CLF-NR ovarian cancer cells, regardless of the presence of BRCA mutations. This concept can offer a personalized approach to therapy that has never been tested before.
- Combining PG545 with PARP inhibition in gynecologic cancer. The other ongoing project involves the use of the heparin sulfate mimetic PG545, combined with PARP inhibitors, in gynecologic cancers. Dr. Shridhar's current study has unveiled promising findings related to the pixatimod (PG545) drug, a sulfated small molecule compound. Engineered with a core structure mimicking heparan sulfate, this compound targets heparanase and heparin binding growth factor signaling. Previous research has demonstrated PG545's potential by enhancing chemotherapy responses through the inhibition of growth factor-mediated signaling in ovarian cancer and exhibiting anti-cancer activity in various preclinical models of breast, prostate and lung cancer. Dr. Shridhar's present study has revealed a previously unknown effect of PG545 in ovarian cancer cells, inducing DNA damage. The investigation unveiled that PG545 induces both single- and double-strand breaks in DNA, while also promoting the autophagic degradation of RAD51 — a critical DNA repair protein. Therefore, this impedes the homologous recombination repair pathway in cancer cells.
Significance to patient care
Many cancer deaths from solid tumors are due to tumors not responding to treatment or developing resistance to therapy. Dr. Shridhar's research focuses on testing new compounds, repurposed drugs and drug combinations in preclinical mouse models. This work aims to support clinical trials and enhance the treatment options available for these patients.
Professional highlights
- Academic editor, Cancers, 2022-present.
- Member, Editorial Board, PLoS One, 2016-2018.
- Senior member, Editorial Board, American Journal of Cancer Research, 2011-2014.