Combination Therapies Explored in Pancreatic Cancer Subgroups

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

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.

Unfortunately, clinical efforts to target angiogenesis in cancer have mostly failed due, in part, to inadequate consideration of the complexity of this biological process, as most efforts targeting angiogenesis in cancer have focused on a single pathway involving vascular endothelial growth factor A (VEGF-A). For example, the anti-VEGF-A monoclonal antibody bevacizumab has been approved for the treatment of platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in combination with chemotherapy; persistent, recurrent, or metastatic cervical cancer in combination with chemotherapy; metastatic colorectal cancer in combination with chemotherapy; metastatic renal cell carcinoma in combination with interferon alpha; glioblastoma as a second-line therapy; and non—small cell lung cancer in combination with chemotherapy.

However, multiple phase II or III trials combining bevacizumab with different chemotherapy regimens in localized to advanced PDAC have not yielded favorable objective responses or improvements in overall survival. Nonetheless, the combination of bevacizumab, erlotinib, and gemcitabine in metastatic PDAC produced a 1-month improvement in progression-free survival (HR 0.72 [0.61-0.86]) over erlotinib and gemcitabine alone.

Additional antiangiogenic agents that have been tried in human PDAC include the small-molecule tyrosine kinase inhibitors axitinib, sunitinib, sorafenib, and vatalanib, as well as the recombinant proteins ziv-aflibercept and elpamotide.

Axitinib and sorafenib have both been tested in phase III trials and neither resulted in improvements in progression-free or overall survival in advanced PDAC patients. In phase II trials, sunitinib did poorly both as a first-line therapy in combination with gemcitabine in locally advanced or metastatic PDAC patients as compared with gemcitabine alone and also as a second-line therapy in metastatic PDAC patients. However, in a second phase II trial, it improved progression-free survival by 1.2 months (HR, 0.51 [0.29-0.89]) in metastatic PDAC patients when used as maintenance therapy for patients who did not progress after first line chemotherapy as compared with observation alone. In another phase II trial, vatalanib showed a favorable 6-month survival rate of 29% compared with historic controls, but this was only a single-arm trial.

Lastly, ziv-aflibercept is a recombinant fusion protein consisting of the extracellular portions of VEGFR-1 and VEGFR-2 that works by trapping VEGF-A, VEGF-B, and placenta growth factor (PlGF), while elpamotide is a VEGFR-2 peptide that works as an immunogen to enhance cancer immunotherapy by inducing a cellular immune response against VEGFR-2—expressing endothelial cells. When these agents were combined with gemcitabine in phase III trials of advanced or metastatic PDAC patients, they failed to improve progression-free or overall survival compared with gemcitabine alone.

We suggest that using combinatorial therapies to target tumor angiogenesis in a subgroup of PDAC patients whose cancers express a strong proangiogenic gene signature and SMAD4-positive cancer cells could suppress aberrant angiogenesis, promote vascular normalization, and interrupt angiocrine pathways that transmit mitogenic signals to pancreatic cancer cells, thereby resulting in improved therapeutic efficacy.