Combination Intraperitoneal Local Delivery of PARPi Implants and Anti-PDL1
Abstract
More than 85% of OC patients relapse with a higher-grade, often metastatic disease with limited treatment options. While each case is expected to present a very different disease profile, there is emerging evidence that specific genetic mutations can render a large subset of these tumors more sensitive to treatment. The most commonly known are the BRCA1 and BRCA2 genes, which normally help repair damaged DNA or kill cells when the DNA cannot be repaired. Mutation or inactivation of these genes results in uncontrolled DNA repair and continued survival of cancer cells. Thus, inhibition of DNA repair through the use of drugs that block PARP activity promotes cancer cell death. The goal of the proposed work is to develop a novel treatment for high grade serous metastatic ovarian cancer that will target the DNA repair pathway in combination with immunomodulation, lower systemic toxicity, and synergization. The PARP inhibitor (PARPi) Talazoparib (TLZ) that blocks DNA repair has proven antitumor activity in patients with both inherited BRCA1/2 mutations and non-inherited inactivation of BRCA1/2 genes. TLZ has been approved for clinical use in breast cancer and is being tested in clinical trials for many other cancers, including ovarian cancer. TLZ has shown to be 100-fold more potent at PARP trapping leading to stronger synthetic lethality and induces DNA damage and STING modulation in ovarian cancers regardless of BRCAness, thus expanding the scope of TLZ PARPi beyond BRCA-patients. However, up to 80% of patients suffer significant side effects associated with PARPi systemic administration, including myelosuppression, nausea, and fatigue, forcing a reduction in the dose below the clinically therapeutic level. To overcome this toxicity, my team has prepared a sustained delivery depot of TLZ called InCeT-TLZ and showed excellent therapeutic efficacy with minimal toxicity for treating established tumors in metastatic ovarian cancer (mOC) and breast cancer models. The proposed InCeT-TLZ will be able to deliver TLZ released over several days directly to the peritoneal cavity to treat mOC rather than distributing systemically. PARPi resistance is a key manifestation in patients, often constraining treatment efficacy. Recent clinical trials highlighted the increased potential for overlapping toxicities of myelosuppression when combining systemic PARPi and immunomodulators or small molecule inhibitors. The highly toxic nature of systemic PARPi limits its potential for therapeutic efficacy as a first-line monotherapy and a combinatorial drug. With the use of InCeT- TLZ we avoid systemic toxicity and can evaluate the combinatorial approach of a dual innate and adaptive modulatory nanoformulation (NanoSTING-PDL1). This formulation combines a STING agonist liposomal formulation with anti-PDL1 targeting as a multi-pronged approach. The proposed study seeks to develop effective combinations of sustained release InCeT-TLZ with immunomodulatory factors, anti-PDL1 and STING agonist, to synergize and minimize systemic toxicity in a patient-mimicking, peritoneal, metastatic, high-grade serous ovarian cancer model. Our central hypothesis is that InCeT-TLZ administered as a sustained release implant intraperitoneally will minimize toxicities to non-target organs, improve drug bioavailability, delay or suppress tumor progression, and allow for safer combinatorial treatment options. The InCeT-TLZ implants has several innovative features that allow for a tailored release profile to accommodate different disease stratifications, can be modulated to include other drugs or used in combination with conventional therapy, and can treat the metastatic sites locally while avoiding systemic toxicity. Additionally, to our knowledge, the approach to administer a nanoformulation of NanoSTING-PDL1 combining the immune modulation of the innate and adaptive system in one delivery is unique. The delivery of a nanoformulation approach allows for
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310274
Entities
People
- Needa Brown
Organizations
- Northeastern University
- United States Army