Combination Therapies Explored in Pancreatic Cancer Subgroups

Murray Korc, MD
Published: Friday, Mar 25, 2016
Murray Korc, MD
Murray Korc, MD
 
Myles Brand Professor of Cancer Research
Professor, Medicine, Biochemistry and Molecular Biology
Indiana University School of Medicine
Director, Pancreatic Cancer Signature Center
Strategic Partnership
To address the unmet need for better diagnostic and therapeutic modalities in pancreatic cancer, investigators at the Indiana University School of Medicine (IUSM) have established the Pancreatic Cancer Signature Center (PCSC) at the Indiana University Melvin and Bren Simon Cancer Center (IUSCC). The PCSC includes investigators from IU, the IU Simon Cancer Center, Purdue University, and the University of Notre Dame.

Pancreatic ductal adenocarcinoma (PDAC) is a deadly, treatment recalcitrant malignancy with a 7% overall 5-year survival rate. It is expected to become the second leading cause of cancer death in the United States in the next decade. Developing and improving therapies for patients with pancreatic cancer using a multitargeted, multi-investigator approach in a manner that fosters team science and that facilitates the nurturing of junior faculty members toward a career in pancreatic cancer research is needed if progress against this disease is to be made. Together, these activities will markedly increase patient survival and quality of life, establishing therapeutic paradigms that will also positively impact the treatment of other cancers.

The PCSC’s mission is to advance knowledge from bench-to-bedside-to practice in a bi-directional manner that facilitates a consistent and productive multidisciplinary exchange of ideas between clinicians, clinical investigators, physician- scientists, and basic scientists. It is anticipated that these interdisciplinary collaborations will lead to improved understanding of the pathobiology of pancreatic cancer and will promote novel approaches for the early diagnosis, prevention, and treatment of this malignancy.

For example, PDAC is a highly desmoplastic cancer that is classically considered as being relatively avascular. By contrast, pancreatic neuroendocrine tumors (PNETs) are not desmoplastic and tend to be highly vascular.

To understand the reasons for these differences, Jesse Gore, PhD, an assistant research professor in the Department of Medicine, and Kelly Craven, MD-PhD student at IUSM, have examined the PDAC transcriptome data bases from The Cancer Genome Atlas (TCGA) and compared this transcriptome with that of PNETs. This analysis revealed the presence of a strong proangiogenesis gene signature in an astounding 35% of PDAC cases, with the remaining cases exhibiting moderate or weak proangiogenic gene signatures.

Despite overlap, the transcriptome in the highangiogenesis PDAC group was distinct from the angiogenic genes upregulated in PNETs. The high-angiogenesis PDAC cases also exhibited a strong transforming growth factor beta (TGF-β) gene signature, which is consistent with the concept that TGF-β promotes tumor angiogenesis in PDAC. This was confirmed by using a tissue microarray (TMA) of human PDACs, which revealed a positive correlation between strong SMAD4 immunoreactivity in the cancer cells and enhanced microvessel density (MVD).

PDACs in TCGA, but not in PNETs, are also enriched in genes that have been associated with inflammation as well as with JAK/STAT3 signaling. Moreover, in vitro studies demonstrated that pancreatic cancer cells (PCCs) release multiple factors that enhance the proliferation of endothelial cells, suggesting that combinatorial antiangiogenic therapy would be required in PDAC to suppress endothelial cell proliferation.

Surprisingly, culturing murine and human PCCs with murine-derived SV40-transformed vascular endothelial cells (SVECs) and human umbilical vascular endothelial cells (HUVECs), respectively, promotes PCC proliferation. This novel angiocrine mechanism was not previously known to occur in PDAC and is mediated by JAK/STAT3 signaling in SVECs and by dual TGF-β and JAK/STAT3 signaling in HUVECs.


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Online CME Activities
TitleExpiration DateCME Credits
Oncology Briefings™: Integrating Novel Targeted Treatment Strategies to Advance Pancreatic Cancer CareNov 30, 20181.0
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