While progress in clinical therapeutics for pancreatic adenocarcinoma has been observed, it has been incremental and modest at best.(1) Until recently, single-agent gemcitabine has been a default standard of care, despite challenges by trials in combination with other therapies. Recently, however, combinations such as FOLFIRINOX, or gemcitabine and nab-paclitaxel, are displacing gemcitabine as front-line therapy for advanced disease.(2) Resistance and metastasis remain major factors in mortality.
More encouraging is the increase in understanding of the molecular pathogenesis, genetics, and epidemiology in pancreatic adenocarcinoma, along with the results of translational research.(1) Together, these advances provide new directions for research and additional targets for therapeutic agents. For example, a preliminary analysis of 24 pancreatic adenocarcinomas revealed that in a core set of 12 cellular signaling pathways and processes there was an average of 63 genetic alterations, mostly point mutations.(3) Current research focuses on developing agents that target specific vulnerabilities both in known germline mutations and in somatic mutations of individual tumors.
Researchers from our Hepatopancreatobiliary Disease Management Team currently direct more than ten clinical trials for pancreatic adenocarcinoma and neuroendocrine cancers. These trials range from epidemiologic/genetic risk assessment studies to evaluation of radiologic assessment methods and evaluation of novel therapeutic agents. Three studies regarding targeted therapy for pancreatic adenocarcinomas are highlighted below.
Gemcitabine and Cisplatin in Combination with Veliparib in Patients with Locally Advanced or Metastatic Pancreatic Adenocarcinoma and BRCA/PALB2 Mutation
Although it is well known that BRCA and PALB2 gene mutations are associated with a heightened risk of breast and ovarian cancers, it is less well known that these mutations are also associated with pancreatic adenocarcinoma.(4) Also, certain BRCA-associated cancers, and potentially pancreatic adenocarcinoma, have been shown to have greater sensitivity to platinum agents when combined with poly-ADP-ribose polymerase (PARP) inhibitors. Because PARP is an essential enzyme that plays a role in recognition and repair of DNA damage, BRCA- and PALB2-mutated tumor cells may be induced to overexpress and thereby become more dependent on PARP for DNA repair. We expect that certain genetically selected pancreatic adenocarcinoma tumors will also be more sensitive to platinum-containing agents (such as cisplatin) when combined with a PARP inhibitor. In addition, tumor cell death may be achieved with doses of PARP inhibitors that are not harmful to cells that still retain BRCA function. Our group recently published a review of clinical features and outcomes of a small series of patients treated at Memorial Sloan Kettering that demonstrated strong support for further evaluation of addition of PARP inhibitors to platinum-based therapy in genetically selected pancreatic adenocarcinoma patients.(5)
This current multisite trial (IRB #12-045) is designed to evaluate the safety and efficacy of veliparib (ABT-888), an orally bioavailable PARP inhibitor, when added to a standard combination therapy of gemcitabine and cisplatin in patients with locally advanced or metastatic pancreatic adenocarcinoma who have either a BRCA or PALB2 mutation. In part I, the primary objective is to compare the response to gemcitabine and cisplatin in combination with veliparib, with gemcitabine and cisplatin alone. In part II, a parallel study, the primary objective is to evaluate the response to single-agent veliparib in patients who have received prior therapy for pancreatic adenocarcinoma. Patients from part I whose cancer does not respond to gemcitabine and cisplatin alone may be eligible for part II. Extensive correlative investigation, stemming from these studies, is underway regarding a detailed understanding of BRCA-related pancreas cancer and is being conducted in collaboration with Dr. Maeve Lowery, Dr. Mary Ellen Moynahan, and other investigators.
M402 in Combination with Gemcitabine in Patients with Newly Diagnosed Metastatic Pancreatic Adenocarcinoma
Anecdotal reports of prolonged survival in cancer patients administered heparin for treatment of venous thrombosis have intrigued researchers over the last four decades.(6) More recent studies have indicated reduced rates of thrombosis and possible survival impact in the groups of pancreatic adenocarcinoma patients randomized to receive cytotoxic therapy plus heparin anticoagulation. M402 is a novel, noncytotoxic heparan sulfate mimetic engineered from low-molecular-weight heparin to have potent antitumor properties and low anticoagulant activity. M402’s mechanism of action is presumed to be through interference with the tumor-stroma interaction of heparan sulfate glycosaminoglycan (HSGAG)-binding proteins, such as growth factors and chemokines. The agent’s ability to target multiple pathways that modulate tumor progression renders it very attractive for development.
This multicenter trial (#12-078) is designed to evaluate the safety and efficacy of M402 in combination with gemcitabine in newly diagnosed, metastatic pancreatic adenocarcinoma patients. This is one of the first clinical studies in which any form of heparin has been evaluated as an anticancer agent. In two mouse models where M402 was evaluated as monotherapy and in combination with gemcitabine, the combined therapy showed greater efficacy.(7) In part I, the primary objectives are to evaluate the safety and tolerability of M402 in combination with gemcitabine and to determine the dose of M402 to be carried forward. In part II, the primary objective is to compare overall survival in patients treated with gemcitabine plus M402 with patients who receive gemcitabine alone. Given recent data regarding the role of gemcitabine and nab-paclitaxel, the cytotoxic backbone of gemcitabine alone will be amended to the combination.
Obtaining and Characterizing Circulating Tumorigenic Cells and Determining Treatment-Sensitivity Profiles in Patients with Pancreatic Adenocarcinoma
Studies done over the last decade have demonstrated that cancer cells, including tumorigenic cells, may be isolated from the peripheral blood of patients with a wide variety of solid tumors including pancreatic adenocarcinoma. Also, building on initial studies, researchers have provided proof of principle that genetic properties of circulating tumor cells can be used to help predict therapy response and to monitor resistance development.(8) Solid tumors consist of a heterogeneous population of cancer cells that differ in their ability to proliferate and form new tumors. Since in many cases the tumorigenic cells represent a minority of the tumor cell population, agents that would selectively kill the tumorigenic cells may be overlooked in our current screening methods. Such differences in sensitivity to treatments between tumorigenic cells and their nontumorigenic progeny may account for the inability of our current chemotherapy drugs to consistently eradicate solid tumors. Also, with disease progression, there can be additional mutations in some of the cancer cells that may account for an increased pace of progression.
This observational study, conducted by Dr. Kenneth Yu and colleagues, is designed to evaluate the feasibility of obtaining and characterizing circulating tumorigenic cells in patients with unresectable pancreatic adenocarcinoma and of determining treatment-sensitivity profiles. Samples (10 mL) of peripheral venous blood were collected prior to initiation of chemotherapy in 50 patients. Blood samples will be collected again before treatment changes in patients with disease progression. More specifically, the primary objectives are to establish the frequency with which circulating tumorigenic cells can be isolated, enriched, and profiled by comparative genomic hybridization from the peripheral blood of eligible patients; and to establish the frequency with which treatment-sensitivity profiles can be determined from isolated circulating tumorigenic cells. The secondary objectives are to collect information regarding treatment regimens, treatment responses, and progression-free and overall survival where possible; and to assess changes in circulating tumorigenic cell treatment-sensitivity profiles in patients over time. The results are encouraging, showing that isolation and gene expression profiling of tumorigenic cells can be performed reliably in these patients. Preliminary analysis suggests that chemo-sensitivity profiling can reliably predict treatment response and that repeat pharmacogenomic modeling can identify key pathways associated with treatment resistance. The investigators presented their preliminary results at the January 2013 American Society of Clinical Oncology’s Gastrointestinal Cancers Symposium.
We hope that the fruits of this research approach will soon enable oncologists to use the genetic profile of an individual patient’s circulating tumor cells to select targeted treatments, prospectively, for that patient. In addition to improving our understanding of the efficacy of current therapies, the profiling of tumorigenic cells is likely to have an impact on the development of targeted therapeutic agents in the future.