Pancreatic Cancer Genomes: Implications for Clinical Management and Therapeutic Development

Abstract

Pancreatic cancer has become the 3 rd leading cause of cancer death, with little improvement in outcomes despite decades of research. Surgery remains the only chance of cure, yet, only 20% will be alive at 5 years after pancreatic resection. Few chemotherapeutics provide any improvement in outcome, and even then, for approved therapies, the survival benefits are marginal. Genomic sequencing studies of pancreatic cancer have revealed a small set of consistent mutations found in most pancreatic cancers, and beyond that a low prevalence for targetable mutations. This may explain the failure of conventional clinical trial designs to show any meaningful survival benefit, except in small and undefined patient sub-groups. With the development of next generation sequencing technology, genomic sequencing and analysis can be performed in a clinically meaningful turnaround time. This can identify therapeutic targets in individual patients and personalize treatment selection.Incorporating pre-clinical discovery and molecularly guided therapy into clinical trial design has the potential to significantly improve outcomes in this lethal malignancy. In this review, we discuss the findings of recent large scale genomic sequencing projects in pancreatic cancer and the potential relevance of these data to therapeutic development.3

Strategies for Increasing Pancreatic Tumor Immunogenicity

“…Although single-agent immunotherapies have failed to show benefit in PDAC, increasing data support the testing of combinatorial approaches that target multiple suppressive mechanisms. In addition to examining genetic mutations in PDAC tumor samples, which is reviewed by Dreyer and colleagues in this CCR Focus Issue (28), performing RNA sequencing to determine which immune escape mechanisms are upregulated (e.g. PD-1, IDO) may allow us to further personalize therapy for patients by combining immunotherapy agents with chemotherapy to reset the immune system (29).…”

Re-engineering the Pancreas Tumor Microenvironment: A "Regenerative Program" Hacked

“…As might be expected of any pathology arising through random mutation, DNA sequence analysis of PDACs reveals them to comprise many, highly genetically diverse clonal clades (3–5). Such diversity, together with the well-known proclivities of pancreatic cancers to adapt, evolve and relapse in response to treatment, has occasioned a huge effort to catalog and categorize them – with the holy grail being effective personalized therapy designed around each tumor’s unique qualities.…”

“…Because Myc and Ras serve as convergent downstream effectors for the diverse upstream driver mutations that cause cancer, targeting them offers a therapeutic strategy, potentially synergizing with the current therapeutics and ongoing clinical trials discussed in this CCR Focus section (2, 5, 45). Indeed, our own and others’ studies using switchable variants of oncogenic Myc and Ras in multiple tumor types (46–53) demonstrate that de-activation of either Myc or KRas G12D triggers rapid and profound regression in many diverse types of experimental tumors in mice, including PDAC (54–56).…”

Chemotherapy, host response and molecular dynamics in periampullary cancer: the CHAMP study

“…However, apart from the prognostic information provided by standard histopathological parameters, no predictive biomarkers for response to neoadjuvant, adjuvant or palliative chemotherapy have yet been introduced into clinical practice. Moreover, although the vast majority of pancreatic cancers contain somatic mutations, there is still a complete lack of "actionable" molecular targets, also immunotherapy has not as yet yielded any substantial clinical benefit for patients with pancreatic cancer [3,4].…”