New Approaches to the Treatment of Pancreatic Cancer
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New Approaches to the Treatment of Pancreatic Cancer From Tumor-Directed Therapy to Immunotherapy Maeve A. Lowery and Eileen M. O’Reilly Department of Medicine, Gastrointestinal Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
Abstract
The development of novel therapeutic strategies for pancreatic adenocarcinoma (PAC) has traditionally been considered particularly challenging for clinical and laboratory investigators due to its aggressive underlying biology and inherent resistance to currently available therapies. More recently, however, advances have been made in the identification of promising therapeutic targets for intervention, along with several key insights into the complex sequence of genetic alterations involved in the evolution of PAC from premalignant precursor lesion to malignant cells with metastatic potential. FOLFIRINOX (5-fluorouracil/ leucovorin/irinotecan/oxaliplatin) has recently been identified as a combination cytotoxic therapy associated with a significant survival benefit over single-agent gemcitabine in good performance status patients with advanced disease; it is hoped that a similar benefit will be seen in planned trials of FOLFIRINOX as perioperative therapy. The success of immune therapy with the anti-cytotoxic T-lymphocyte antigen-4 antibody ipilimumab in advanced melanoma has spurred interest in the development of vaccines and immune therapies for other solid tumors. Certainly, the concept of harnessing the power of the immune system for cancer treatment is an attractive concept to patients and clinicians alike. Herein we discuss recent advances in the development of novel therapeutic approaches to PAC, focusing in particular on recent developments in immune and vaccine therapy.
1. Genomic Analysis of Pancreatic Adenocarcinoma Comprehensive exomic sequencing of the genome of 24 human pancreatic cancers has yielded important information regarding the molecular signature of pancreatic adenocarcinoma (PAC).[1] A wide variety of genetic mutations were identified that exhibited extensive interpatient heterogeneity, but had a common effect of driving 12 key cell signaling pathways responsible for invoking pancreatic tumorigenesis. More recently, published data have offered considerable insights into the genetic evolution of metastatic pancreatic cancer, suggesting that the time to development of distant metastases is substantially longer than clinical experience would suggest.[2] Yachida et al.[2] performed whole genome exomic sequencing on the primary pancreatic tumor and several sites of metastases from seven patients. Several distinct clonal populations were found in the primary tumor and were also identified in metastatic sites, indicating that the genetic heterogeneity of pancreatic metastases reflects that of the primary tumor from which they arise. However, these populations of subclones,
which gave rise to distant metastases, had genetically evolved from an original non-metastatic p
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