Nanoformulations and Sustained Delivery of PARP Inhibitors for Breast Cancer
Abstract
This application responds squarely to the overarching challenge to revolutionize treatment regimens by replacing drugs that have life-threatening toxicities with safe, effective interventions. Thus, the proposed project addresses a fundamental cause for mortality, as discussed in the "Breast Cancer Landscape" document prepared by the Breast Cancer Research Program. We have assembled a strong multidisciplinary breast cancer (BC) research team with expertise in nanomedicine and BC biology to maximize the likelihood of project success. In the United States in 2015, there will be 231,840 new patients diagnosed with BC and 40,290 deaths as a result of BC recurrence or metastasis. 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 poly (ADP-ribose) polymerase (PARP) activity, is thought to promote cancer cell death. Patients that stand to benefit from such mono and combination therapies include those with triple-negative BC (TNBC), of whom 25% have BRCA1/2 mutations and another 50% exhibit "BRCAness." Additionally, of those with HER2-positive BC (one-third of all BC patients), PARP inhibitors are expected to be effective through a different mechanism that is linked to expression of the transcriptional factor NF-kappaB. PARP inhibitors, such as Talazoparib, have shown antitumor activity in patients with both inherited BRCA1/2 mutations and non-inherited inactivation of BRCA1/2 genes. Several PARP inhibitors are currently undergoing Phase 3 clinical trials for treatment of patients with BRCA mutations and other BC subtypes known for DNA misrepair. There is great interest in developing better formulations of these PARP inhibitors to improve the bioavailability and minimize associated toxicities. Talazoparib is only available in oral form and must therefore be taken in higher quantities than required because of the poor bioavailability. Up to 80% of patients suffer significant side effects including bone marrow toxicity, nausea, fatigue, and diarrhea because little of the consumed dose actually reaches the tumor. Due to the combined toxicity, dosage of these agents has to be reduced to levels well below the clinically relevant doses. Injectable nanoformulations would be highly advantageous over oral formulations by offering both enhanced tumor accumulation and reduced side effects. Here we propose to study two injectable formulations that provide different delivery routes for Talazoparib, a potent PAPR inhibitor: An implant, InCeT-Talazoparib, which can be injected directly in the tumor where it will act as a sustained release depot of Talazoparib over a prolonged period of approximately 30 days. It delivers 100% of the drug to the tumor site with almost no systemic toxicity. It can be used for neoadjuvant chemotherapy or as a breast-preserving alternative to radical mastectomy. A nanoparticles-based formulation, T-NanoTalazoparib, specifically designed for the neoadjuvant treatment and maintenance therapy of BC cancer by encapsulating PARP inhibitors inside flexible spheres of nanometer size so that the entire drug dose can be injected directly into the bloodstream. This nanopackaging also improves the probability of drug accumulating in the tumor, since the nanoparticles (1) circulate longer in the blood stream, (2) contain higher concentrations of drug, and (3) can take advantage of biochemical targeting to deliver the drug to the tumor minimizing systemic toxicities. Our central hypothesis is that these Talazoparib formulation
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610732
Entities
People
- Karen Liby
Organizations
- Michigan State University
- United States Army