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A Phase I/II Study of Ivaltinostat Combined with Gemcitabine and Erlotinib in Patients with Untreated Locally Advanced or Metastatic Pancreatic Adenocarcinoma

ABSTRACT: Histone deacetylase inhibitors (HDACi) are currently used as anticancer drugs; however, no clinical trials proved efficacy in pancreatic adenocarcinoma (PDAC). Ivaltinostat, a novel intravenous HDACi, presented cell growth inhibition and improved chemo-sensitivity in PDAC. This phase I/II study demonstrated ivaltinostat with gemcitabine and erlotinib can be administered safely to improve survivals in patients with untreated advanced PDAC. In addition, we proposed potential blood markers to predict response to ivaltinostat treatment based on correlative studies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE189724 | GEO | 2021/11/29

REPOSITORIES: GEO

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Project description:Chemoresistance to gemcitabine limits its clinical implementation for pancreatic ductal adenocarcinoma (PDAC). We previously generated an antibody drug conjugate (ADC) -like agent, EGFR/HER2 dual-targeting ligand-based lidamycin (DTLL), and studied the effect of DTLL combined with gemcitabine and the potential role of SMAD4 in the chemoresistance of PDAC. On the basis of SMAD4 profiles in in vitro and in vivo models, we investigated the antitumor effects of DTLL, gemcitabine and their combination, followed with mechanistic characterization. The results suggested that DTLL combination treatment with gemcitabine significantly repressed tumors with remarkably enhanced efficacy as compared to gemcitabine or DTLL alone given in either SMAD4-deficient/gemcitabine-resistant or SMAD4-sufficient/gemcitabine-sensitive cell line derived xenograft (CDX) and patient derived xenograft (PDX) tumors, respectively. Functional studies indicated that SMAD4 genetic status is responsible for SMAD4 protein level which determines different cellular susceptibility of PDAC. R100T mutation contributes to loss of SMAD4 protein and function with rapid protein degradation, leading to resistance to gemcitabine in PDAC cells. Moreover, DTLL significantly altered the protein half-life time and level of mutant and wild-type SMAD4 by inhibiting protein degradation at different velocities and distinctly changing the interaction of SMAD4 with TRIM33. Mechanism studies implied that DTLL combinational treatment might not only prevent from neoplastic proliferation via blockage of ATK/mTOR signaling and anti-apoptotic proteins (Bcl-2 and MCL1) mediated by impaired NF-B function in SMAD4-sufficient/gemcitabine-sensitive PDAC cells, but also restore the bioactivity of SMAD4 as a tumor suppressor to trigger its downstream NF-B-regulated signaling of cell apoptosis in SMAD4-deficient/gemcitabine-resistant tumors. In conclusion, SMAD4 is the key central mediator of not only the occurrence and development but also susceptibility in PDAC. DTLL sensitized gemcitabine efficacy via distinct action mechanisms based on SMAD4 profiles in SMAD4-sufficient/gemcitabine-sensitive and SMAD4-deficient/-resistant PDAC, respectively. Our findings provide insight into a rational SMAD4-directed precision treatment strategy and reveal a promising DTLL combination therapy to overcome chemoresistance in gemcitabine-resistant PDAC.

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A Phase I/II Study of Ivaltinostat Combined with Gemcitabine and Erlotinib in Patients with Untreated Locally Advanced or Metastatic Pancreatic Adenocarcinoma

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