Promising New Therapies in Advanced Pancreatic Adenocarcinomas

Kundranda, Madappa N.; Kachaamy, Toufic

doi:10.2217/fon.14.197

Cited by 10 publications

(8 citation statements)

References 71 publications

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“…Thus, our finding may provide an explanation for the ineffectiveness of single signal inhibition of the Hh and c-Met pathways (53). Controversial data have been reported on the role of Hh signaling and stromal depletion.…”

Section: Discussionmentioning

confidence: 74%

Heterogeneous Stromal Signaling within the Tumor Microenvironment Controls the Metastasis of Pancreatic Cancer

et al. 2017

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Understanding how stromal signals regulate the development of pancreatic ductal adenocarcinoma (PDAC) may suggest novel therapeutic interventions in this disease. In this study, we assessed the metastatic role of stromal signals suggested to be important in the PDAC microenvironment. Src and IGF-1R phosphorylated the pro-metastatic molecule Annexin A2 (AnxA2) at Y23 and Y333 in response to stromal signals HGF and IGF-1, respectively, and IGF-1 expression was regulated by the Sonic Hedgehog (Shh) pathway. Both Shh and HGF were heterogeneously expressed in PDAC stroma, and only dual inhibition of these pathways could significantly suppress AnxA2 phosphorylation, PDAC growth and metastasis. Taken together, our results illuminate tumor-stromal interactions which drive metastasis, and provide a mechanism-based rationale for a stroma-directed therapy for PDAC.

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Section: Discussionmentioning

confidence: 74%

Heterogeneous Stromal Signaling within the Tumor Microenvironment Controls the Metastasis of Pancreatic Cancer

et al. 2017

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“…Most patients present with metastatic disease at diagnosis and have only a 2% five-year survival (2). To date, the rate of successful clinical trials in pancreatic cancer remains low (8). Of the many therapies investigated in large clinical trials over the past two decades, only two systemic therapies have demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) as compared to gemcitabine alone (9,10).…”

Section: Introductionmentioning

confidence: 99%

Strategies for Increasing Pancreatic Tumor Immunogenicity

Johnson

Yarchoan

Lee

et al. 2017

Clinical Cancer Research

141

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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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“…Even when the disease is diagnosed at an early stage, the prognosis is dismal [1]. In metastatic disease, modern chemotherapy regimens such as FOLFIRINOX and nab-paclitaxel plus gemcitabine produce median survival times of less than a year [3, 4], underscoring the urgent need for novel therapies [5]. Despite many agents tested, only the EGFR tyrosine kinase inhibitor erlotinib has gained FDA approval in combination with gemcitabine [6], based on a 2-week improvement in survival compared to gemcitabine alone [7, 8].…”

Section: Introductionmentioning

confidence: 99%

Vaccination with poly(IC:LC) and peptide-pulsed autologous dendritic cells in patients with pancreatic cancer

et al. 2017

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BackgroundDendritic cells (DCs) enhance the quality of anti-tumor immune response in patients with cancer. Thus, we posit that DC-based immunotherapy, in conjunction with toll-like receptor (TLR)-3 agonist poly-ICLC, is a promising approach for harnessing immunity against metastatic or locally advanced unresectable pancreatic cancer (PC).MethodsWe generated autologous DCs from the peripheral blood of HLA-A2+ patients with PC. DCs were pulsed with three distinct A2-restricted peptides: 1) human telomerase reverse transcriptase (hTERT, TERT572Y), 2) carcinoembryonic antigen (CEA; Cap1-6D), and 3) survivin (SRV.A2). Patients received four intradermal injections of 1 × 107 peptide-pulsed DC vaccines every 2 weeks (Day 0, 14, 28, and 42). Concurrently, patients received intramuscular administration of Poly-ICLC at 30 μg/Kg on vaccination days (i.e., day 0, 14, 28, and 42), as well as on days 3, 17, 21, 31, 37, and 45. Our key objective was to assess safety and feasibility. The effect of DC vaccination on immune response was measured at each DC injection time point by enumerating the phenotype and function of patient T cells.ResultsTwelve patients underwent apheresis: nine patients with metastatic disease, and three patients with locally advanced unresectable disease. Vaccines were successfully manufactured from all individuals. We found that this treatment was well-tolerated, with the most common symptoms being fatigue and/or self-limiting flu-like symptoms. Among the eight patients who underwent imaging on day 56, four patients experienced stable disease while four patients had disease progression. The median overall survival was 7.7 months. One patient survived for 28 months post leukapheresis. MHC class I –tetramer analysis before and after vaccination revealed effective generation of antigen-specific T cells in three patients with stable disease.ConclusionVaccination with peptide-pulsed DCs in combination with poly-ICLC is safe and induces a measurable tumor specific T cell population in patients with advanced PC.Trial registration NCT01410968; Name of registry: clinicaltrials.gov; Date of registration: 08/04/2011).Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-017-0459-2) contains supplementary material, which is available to authorized users.

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Promising New Therapies in Advanced Pancreatic Adenocarcinomas

Cited by 10 publications

References 71 publications

Heterogeneous Stromal Signaling within the Tumor Microenvironment Controls the Metastasis of Pancreatic Cancer

Heterogeneous Stromal Signaling within the Tumor Microenvironment Controls the Metastasis of Pancreatic Cancer

Strategies for Increasing Pancreatic Tumor Immunogenicity

Vaccination with poly(IC:LC) and peptide-pulsed autologous dendritic cells in patients with pancreatic cancer

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