Phase 2 study of vismodegib, a hedgehog inhibitor, combined with gemcitabine and nab-paclitaxel in patients with untreated metastatic pancreatic adenocarcinoma

Jesus-Acosta, Ana De; Sugar, Elizabeth A.; O’Dwyer, Peter J.; Ramanathan, Ramesh K.; Hoff, Daniel D. Von; Rasheed, Zeshaan A.; Li, Zheng; Begum, Asma; Anders, Robert A.; Maitra, Anirban; McAllister, Florencia; Rajeshkumar, N. V.; Yabuuchi, Shinichi; Wilde, Roeland F. de; Batukbhai, Bhavina; Şahin, İsmet; Laheru, Daniel A.

doi:10.1038/s41416-019-0683-3

Cited by 117 publications

(77 citation statements)

References 38 publications

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“…It can also suppress pancreatic CSC proliferation and survival by inhibiting Hh signaling pathways [90]. In a phase II trial, vismodegib combined with gemcitabine and nab-paclitaxel was used against untreated metastatic pancreatic cancer [91]. In another phase Ib/II trial, vismodegib plus gemcitabine was used to treat metastatic pancreatic cancer [92].…”

Section: Hh Signaling Pathway Inhibitorsmentioning

confidence: 99%

Emerging agents that target signaling pathways in cancer stem cells

et al. 2020

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Cancer stem cells (CSCs) contribute to the initiation, recurrence, and metastasis of cancer; however, there are still no drugs targeting CSCs in clinical application. There are several signaling pathways playing critical roles in CSC progression, such as the Wnt, Hedgehog, Notch, Hippo, and autophagy signaling pathways. Additionally, targeting the ferroptosis signaling pathway was recently shown to specifically kill CSCs. Therefore, targeting these pathways may suppress CSC progression. The structure of small-molecule drugs shows a good spatial dispersion, and its chemical properties determine its good druggability and pharmacokinetic properties. These characteristics make small-molecule drugs show a great advantage in drug development, which is increasingly popular in the market. Thus, in this review, we will summarize the current researches on the small-molecule compounds suppressing CSC progression, including inhibitors of Wnt, Notch, Hedgehog, and autophagy pathways, and activators of Hippo and ferroptosis pathways. These small-molecule compounds emphasize CSC importance in tumor progression and propose a new strategy to treat cancer in clinic via targeting CSCs.

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Section: Hh Signaling Pathway Inhibitorsmentioning

confidence: 99%

Emerging agents that target signaling pathways in cancer stem cells

et al. 2020

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“…In a phase II trial, vismodegib has suggested efficacy in some pediatric patients with medulloblastoma [193]. Conversely, no clinical benefit was observed in phase II trials in other tumors including: PDAC [194,195], colorectal cancer [196], gastric and gastroesophageal junction carcinoma [197], small cell lung cancer [198], and ovarian cancer [199]. On the contrary, sonidegib showed possible efficacy in triple negative breast cancer patients in a phase I trial [200].…”

Section: Ccn2mentioning

confidence: 99%

Cancer-Associated Fibroblasts: Versatile Players in the Tumor Microenvironment

Ganguly

Chandra

Karalis

et al. 2020

Cancers

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Cancer-associated fibroblasts (CAFs) are indispensable architects of the tumor microenvironment. They perform the essential functions of extracellular matrix deposition, stromal remodeling, tumor vasculature modulation, modification of tumor metabolism, and participation in crosstalk between cancer and immune cells. In this review, we discuss our current understanding of the principal differences between normal fibroblasts and CAFs, the origin of CAFs, their functions, and ultimately, highlight the intimate connection of CAFs to virtually all of the hallmarks of cancer. We address the remarkable degree of functional diversity and phenotypic plasticity displayed by CAFs and strive to stratify CAF biology among different tumor types into practical functional groups. Finally, we summarize the status of recent and ongoing trials of CAF-directed therapies and contend that the paucity of trials resulting in Food and Drug Administration (FDA) approvals thus far is a consequence of the failure to identify targets exclusive of pro-tumorigenic CAF phenotypes that are mechanistically linked to specific CAF functions. We believe that the development of a unified CAF nomenclature, the standardization of functional assays to assess the loss-of-function of CAF properties, and the establishment of rigorous definitions of CAF subpopulations and their mechanistic functions in cancer progression will be crucial to fully realize the promise of CAF-targeted therapies.

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“…Finally, the hedgehog signaling pathway involving the Sonic Hedgehog (SHH) proteins promoted desmoplasia [ 107 ] and stimulated stellate cell differentiation and myofibroblast activation in pancreatic cancer. SHH inhibition showed promising results in mouse models but did not improve OS in clinical trials [ 150 , 151 ]. As hedgehog-signaling CAFs are heterogenous and encompass several subsets [ 6 ], one hypothesis for this failure is the absence of targeting of protumoral CAF subsets.…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

Cancer-Associated Fibroblasts: Accomplices in the Tumor Immune Evasion

Hilmi

Nicolle

Bousquet

et al. 2020

Cancers

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Cancer-associated fibroblasts (CAFs) are prominent cells within the tumor microenvironment, by communicating with other cells within the tumor and by secreting the extracellular matrix components. The discovery of the immunogenic role of CAFs has made their study particularly attractive due to the potential applications in the field of cancer immunotherapy. Indeed, CAFs are highly involved in tumor immune evasion by physically impeding the immune system and interacting with both myeloid and lymphoid cells. However, CAFs do not represent a single cell entity but are divided into several subtypes with different functions that may be antagonistic. Considering that CAFs are orchestrators of the tumor microenvironment and modulate immune cells, targeting their functions may be a promising strategy. In this review, we provide an overview of (i) the mechanisms involved in immune regulation by CAFs and (ii) the therapeutic applications of CAFs modulation to improve the antitumor immune response and the efficacy of immunotherapy.

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Phase 2 study of vismodegib, a hedgehog inhibitor, combined with gemcitabine and nab-paclitaxel in patients with untreated metastatic pancreatic adenocarcinoma

Cited by 117 publications

References 38 publications

Emerging agents that target signaling pathways in cancer stem cells

Emerging agents that target signaling pathways in cancer stem cells

Cancer-Associated Fibroblasts: Versatile Players in the Tumor Microenvironment

Cancer-Associated Fibroblasts: Accomplices in the Tumor Immune Evasion

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