Northeastern University


Behavioral Neuroscience, '24

Nano-formulations and Sustained Delivery of Combination Therapy of TLZ with CER or ALP to Overcome PARPi Resistance for Ovarian Cancer Treatment

Mentor: Srinivas Sridhar, Ph.D.

Institution: Northeastern University

Previous research has shown that using poly(ADP-ribose) polymerase inhibitors (PARPi) to treat cancers with mutations that result in a homologous recombination deficiency, such as ovarian cancers with the BRCA1/2 mutations, is very effective. The drug used in this research was Talazoparib (TLZ) for its effectiveness as a PARPi, and the cancer of focus was high grade serious ovarian cancer (HGSOC). The alternative drug delivery method of implants loaded with TLZ (InCeT-TLZ ) that can be directly implanted into the tumor or peritoneal cavity for a slow release of the drug directly at the intended site has also been proven as more effective in both treatment and reducing cytotoxic side effects. Previous in vivo studies on have unfortunately resulted in the mice becoming resistant to TLZ, rendering the treatment no longer effective after a time. To combat this, current research is investigating combination therapy using TLZ and a companion drug delivered intraperitoneally via implant over at least 30 days. It is expected that this will lead to better bioavailability, delayed or suppression of tumor progression, and control ascites. The effectiveness of two drugs Ceralasertib (CER) and Alpeisib (ALP) will be tested in combination with TLZ in both in vitro and in vivo studies. The in vitro studies will use two mouse cell lines that model HGSOC (3666, BPPNM) to optimize the combination therapies, looking at the survivability of the cells in each treatment group at various doses. IC50, synergism, and western blot will be used to assess effectiveness of the treatments. In vivo studies on the sustained delivery of InCeT-TLZ + InCeT-CER or InCeT-TLZ + InCeT-ALP using murine models of HGSOC. Tumor fold change, tumor growth inhibition and delay, survival curve, body weight assessment, histology, immunohistochemistry, blood smear analysis, complete blood count, and blood chemistry will all be examined throughout the study to asses drug efficacy and any cytotoxic effects.