Shannon Puhalla, MD

2012-2013 BCRF Project:
Conquer Cancer Foundation of ASCO 2011 Career Development Award

The development and use of PARP inhibitors as a treatment for patients with cancers related to BRCA 1/2 mutations is exciting and may allow for personalized, precision treatment. The challenge is to prospectively identify which patients will respond. The additional challenge with PARP inhibitors is combining them with chemotherapy, which would allow for applicability to a broader population of patients. The identification of genomic profiles corresponding to alterations in DNA repair that enhance this sensitivity is needed. Moreover, this will allow for greater insights regarding mechanisms of activity of these agents.

In 2012-2013, Dr. Puhalla plans to expand a currently opened and accruing phase I clinical trial investigating the combination of the PARP inhibitor veliparib (ABT-888) with weekly carboplatin and paclitaxel. The trial has nearly completed accrual; enrollment in a mandatory biopsy cohort is planned after determination of the recommended phase II dose of the combination. The biopsy cohort will consist of six to twelve patients with triple negative breast cancer whose tissues will biopsied throughout different phases of treatment cycles. The tissues will be analyzed and will be evaluated for changes in DNA repair pathways that are present at baseline or are altered as a result of chemotherapy and PARP inhibitor treatment.

Mid-year Progress: Dr. Puhalla has multiple trials evaluating the effects of this drug and its metabolism in the body. One of these trials is giving veliparib by itself in patients with cancer who have a BRCA 1/2 mutation and in certain other types of breast and ovarian cancer. In this trial, Dr. Puhalla's team will be testing tumor tissue samples obtained from patients in the study to try to find ways that certain patients may be more or less sensitive to the drug and to make sure that the drug is doing what the researchers expect it to in the tumor tissues.

The other trial Dr. Puhalla's team is working on is combining veliparib with chemotherapy drugs. This study is giving weekly administered paclitaxel and carboplatinum together with veliparib. In this study, they are slowly increasing the dose of veliparib to find the highest and safest dose that can be administered. The researchers hypothesize that because breast cancers that are "triple negative" are molecularly similar to those with BRCA1 mutations, these types of cancers may also be more sensitive to PARP inhibitors. Once they have determined the proper dose to move forward with, Dr. Puhalla's team will enroll 12 patients with triple negative breast cancer who will have biopsies performed before treatment and after one cycle of treatment to determine how the drug is working in the tumor tissues and to try to predict if certain triple negative breast cancers may respond better to this combination than others. Currently, there is one patient left to be enrolled on the escalation cohort. The study was on hold to allow for multiple protocol revisions that were needed to make the combination safer, more tolerable, and more convenient for patients over the long term. Dr. Puhalla anticipates re-opening the trial to enrollment in the next few months.

Bio:
Dr. Puhalla is Assistant Professor of Medicine at the University of Pittsburgh School of Medicine. She maintains a busy practice in breast oncology at Magee-Women's Hospital of UPMC and her research interests include early phase clinical trials in breast cancer. She serves as the liaison between the Molecular Therapeutics and Drug Discovery Program of UPCI and the Breast Cancer Program and she is the principal investigator on NCI and pharma- sponsored phase I/II clinical trials focused in breast cancer. Dr. Puhalla graduated from Northeastern Ohio Universities College of Medicine (NEOUCOM) and performed her Internal Medicine residency and Hematology/Oncology Fellowship at The Ohio State University Medical Center. She was appointed as Breast Cancer Fellow and spent dedicated training in the design of breast cancer phase I and II clinical trials and the care of breast oncology patients. She was appointed to the faculty of the University of Pittsburgh in 2007. Her primary clinical trial interests include novel targeted agents for triple negative breast cancer and reversal of endocrine therapy resistance in estrogen-positive breast cancers. Dr. Puhalla has funding from the National Cancer Institute (ARRA ACTNOW) and the American Society of Clinical Oncology (ASCO Career Development Award). Her work as been published in key medical journals such as the Journal of Clinical Oncology. She also serves on the editorial board for Cancer Chemotherapy and Pharmacology.