Current and Emerging Therapies in Metastatic Pancreatic Cancer

Manji, Gulam A.; Olive, Kenneth P.; Saenger, Yvonne M.; Oberstein, Paul E.

doi:10.1158/1078-0432.ccr-16-2319

Cited by 125 publications

(102 citation statements)

References 76 publications

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“…Specifically, we will (1) examine the challenges in developing successful immunotherapies for PDAC, (2) describe the complex immune components of the TME and discuss how the immune system, pancreatic tumor cells, microbiome, and stromal signals suppress immune-mediated attack, and (3) discuss novel multi-agent therapeutic strategies to target signals within this integrated immunosuppressive network that are under development in clinical trials. Current standard of care therapy and clinical trials in progress are also reviewed by Manji et al in this CCR Focus issue (14). …”

Section: Introductionmentioning

confidence: 99%

Strategies for Increasing Pancreatic Tumor Immunogenicity

Johnson

Yarchoan

Lee

et al. 2017

Clinical Cancer Research

140

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Immunotherapy has changed the standard of care for multiple deadly cancers including lung, head and neck, gastric, and some colorectal cancers. However, single agent immunotherapy has had little effect in pancreatic adenocarcinoma (PDAC). Increasing evidence suggests that the PDAC microenvironment is comprised of an intricate network of signals between immune cells, PDAC cells, and stroma, resulting in an immunosuppressive environment resistant to single agent immunotherapies. In this review, we discuss differences between immunotherapy sensitive cancers and PDAC, the complex interactions between PDAC stroma and suppressive tumor infiltrating cells that facilitate PDAC development and progression, the immunologic targets within these complex networks that are drugable, and data supporting combination drug approaches that modulate multiple PDAC signals, which should lead to improved clinical outcomes.

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Section: Introductionmentioning

confidence: 99%

Strategies for Increasing Pancreatic Tumor Immunogenicity

Johnson

Yarchoan

Lee

et al. 2017

Clinical Cancer Research

140

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“…As devastating as these statistics are, they do not encompass the considerable pain and suffering associated with pancreatic ductal adenocarcinoma (PDAC), the commonest form of pancreatic cancer. Despite intense efforts, progress in improving survival rates for patients with metastatic pancreatic cancer has been modest at best (2). …”

Section: Introductionmentioning

confidence: 99%

“…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).…”

Section: Introductionmentioning

confidence: 99%

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

Evan

Hah

Littlewood

et al. 2017

Clinical Cancer Research

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The “hallmarks” of pancreatic ductal adenocarcinoma (PDAC) include proliferative, invasive and metastatic tumor cells and an associated dense desmoplasia comprised of fibroblasts, pancreatic stellate cells, extracellular matrix and immune cells. The oncogenically-activated pancreatic epithelium and its associated stroma are obligatorily interdependent, with the resulting inflammatory and immune-suppressive microenvironment contributing greatly to the evolution and maintenance of PDAC. The peculiar pancreas-specific tumor phenotype is a consequence of oncogenes hacking the resident pancreas regenerative program, a tissue specific repair mechanism regulated by discrete super enhancer networks. Defined as genomic regions containing clusters of multiple enhancers, super enhancers play pivotal roles in cell/tissue specification, identity and maintenance. Hence, interfering with such super enhancer driven repair networks should exert a disproportionately disruptive effect on tumor versus normal pancreatic tissue. Novel drugs that directly or indirectly inhibit processes regulating epigenetic status and integrity, including those driven by histone deacetylases, histone methyltransferase and hydroxylases, DNA methyltransferases, various metabolic enzymes, and bromodomain and extra-terminal motif proteins (BETs) have shown the feasibility of disrupting super enhancer-dependent transcription in treating multiple tumor types, including PDAC. The idea that pancreatic adenocarcinomas rely on embedded super enhancer transcriptional mechanism suggests a vulnerability that can be potentially targeted as novel therapies for this intractable disease.

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“…However, in spite of expanding options in targeted therapy [8], PDAC has mostly remained-treatment recalcitrant. Moreover, the incidence of PDAC continues to increase slightly due to the aging of the United States population and the high prevalence of obesity and type 2 diabetes [9]. Moreover, it is anticipated that PDAC will become the second leading cause of cancer death in the United States during the 2020’s [10].…”

Section: Tumor Microenvironment In Pdacmentioning

confidence: 99%

Designer hydrogels: Shedding light on the physical chemistry of the pancreatic cancer microenvironment

Lin

Korc

2018

Cancer Letters

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Pancreatic ductal adenocarcinoma (PDAC) is currently the third leading cause of cancer mortality in the United States, with a 5-year survival of ∼8%. PDAC is characterized by a dense and hypo-vascularized stroma consisting of proliferating cancer cells, cancer-associated fibroblasts, macrophages and immune cells, as well as excess matrices including collagens, fibronectin, and hyaluronic acid. In addition, PDAC has increased interstitial pressures and a hypoxic/acidic tumor microenvironment (TME) that impedes drug delivery and blocks cancer-directed immune mechanisms. In spite of increasing options in targeted therapy, PDAC has mostly remained treatment recalcitrant. Owing to its critical roles on governing PDAC progression and treatment outcome, TME and its interplay with the cancer cells are increasingly studied. In particular, three-dimensional (3D) hydrogels derived from or inspired by components in the TME are progressively developed. When properly designed, these hydrogels (e.g., Matrigel, collagen gel, hyaluronic acid-based, and semi-synthetic hydrogels) can provide pathophysiologically relevant compositions, conditions, and contexts for supporting PDAC cell fate processes. This review summarizes recent efforts in using 3D hydrogels for fundamental studies on cell-matrix or cell-cell interactions in PDAC.

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Current and Emerging Therapies in Metastatic Pancreatic Cancer

Cited by 125 publications

References 76 publications

Strategies for Increasing Pancreatic Tumor Immunogenicity

Strategies for Increasing Pancreatic Tumor Immunogenicity

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

Designer hydrogels: Shedding light on the physical chemistry of the pancreatic cancer microenvironment

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