Pancreatic cancer is an intractable malignancy with a 5-year survival rate of just 8%. Unlike in other malignancies, this survival rate has not significantly changed over the last 30 years. The promise of precision medicine is the ability to tailor cancer treatment based on specific cancer-associated alterations detected in an individual patient’s tumor. Given the desperate need for novel therapies for pancreatic cancer, we are attacking the problem through a multi-disciplinary approach.
Mapping Mutations
We are actively characterizing alterations that occur in pancreatic cancer which may be driving cancer formation or progression. We routinely sequence tumor DNA and RNA to identify oncogenic germline or somatic mutations, copy number alterations, and structural variants.
A subset of the alterations that are identified are potentially therapeutically “actionable”, meaning targeted agents exist that may be effective. However, there are very few examples of systematic treatment with targeted agents in pancreatic cancer. An example of the rare and much-needed successof such efforts is the recent approval of the PARP inhibitor Olaparib for metastatic pancreatic cancer patients with a germline mutation in BRCA1/BRCA2.
Science-Driven Clinical Trials
We have had success with a precision oncology approach for individual patients – e.g., treatment of a patient with an activating BRAF deletion with the MEK inhibitor Trametinib and treatment of a patient with a ROS1 translocation with the tyrosine kinase inhibitor (TKI) Crizotinib. We are also focused on developing science-driven clinical trials to test promising new agents in rationally chosen patient populations. Guiding principles for designing these trials include:
- Strong Preclinical Studies, i.e., use of the correct model/models to answer our scientific questions as satisfyingly as possible before bringing to patients
- Strong Correlative Studies, i.e., collection of biopsies and other specimens throughout the course of treatment and intelligent design of studies utilizing these samples to learn as much as possible about the effect of treatment in the clinical setting
An example of this approach is an upcoming series of trials led by Dr. James Cleary, MD, PhD and Dr. Alan D’Andrea, MD and funded by the Pancreatic Cancer Collective exploring combination therapies in patients with DNA damage repair (DDR) pathway defects in pancreatic cancer. The trial design features three arms testing gemcitabine chemotherapy in combination with a different targeted agent – an ATR inhibitor, a CHK1 inhibitor, or a WEE1 inhibitor – in small patient populations allowing for rapid identification of promising combination(s). In addition, correlative studies are being planned with other members of the Hale Center.
