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Pancreatic Cancer Combination Therapy Using a BH3 Mimetic and a Synthetic Tetracycline

Significance Statement

Pancreatic cancer is a devastating disease with minimal effective therapeutic options for patients, necessitating novel treatment strategies. Sabutoclax, a small molecule antagonist of the anti-apoptotic Bcl-2 proteins, and Minocycline, a commonly available antibiotic, display significant biological synergy against pancreatic cancer (PDAC). PDAC is a heterogeneous disease with distinct genetic profiles among patients. This complexity contributes to its inherent aggressive nature and resistance to conventional therapies.  Multiple in vitro and in vivo PDAC models, including immune-competent KPC transgenic mice, with varying genetic backgrounds show susceptibility to this novel therapeutic combination.  This effect is partly mediated through Stat3, a signaling pathway critical for PDAC development and progression.

Bcl-2 proteins contribute prominently to pancreatic cancer cell survival and resistance to apoptosis-inducing agents, making them a critical target.  Previous studies with Minocycline in the context of cancer yielded marginal inhibitory effects, questioning its use as a cancer therapeutic. However, we believe that one aspect of this multi-functional drug, i.e., an ability to protect against apoptosis via upregulation of Bcl-2, was masking its true efficacy against cancer. The ability of Sabutoclax to functionally suppress this effect now uncovers a new toxicity profile for this drug in PDAC.  The use of these two treatments together challenges pancreatic cancer cells in novel ways, producing relevant cancer-selective inhibitory effects.

Sabutoclax is a BH3 mimetic that works at much lower concentrations (nanomolar range) than other small molecules targeting the Bcl-2 proteins, which can translate into both achievable plasma concentrations in vivo as well as lower toxicity profiles.  Additionally, preliminary studies show that Sabutoclax has a low toxicity profile, a prerequisite for an effective therapeutic.

The most significant aspects of this study are the biological responses in PDAC cells treated with Sabutoclax and Minocycline. In translational cancer research, biological efficacy is of utmost importance. Underlying mechanisms of action are relevant, but ultimately mean little if the drugs do not work.  This unique therapeutic combination does, indeed, show encouraging results and warrants additional exploration.  This study serves as a foundation for a novel avenue of research in combating PDAC, one that removes the advantages provided to cancer cells by the anti-apoptotic Bcl-2 proteins and uncovers unique therapeutic potential of a classical family of antibiotics for cancer therapy. Future studies will lead to improvements of this combination as well as insights into the full mechanism(s) underlying the action of these compounds that in combination provide an effective therapy for PDAC.

Journal Reference

Cancer Res. 2015 Jun 1;75(11):2305-15.

Quinn BA1, Dash R2, Sarkar S1, Azab B3, Bhoopathi P1, Das SK4, Emdad L5 , Wei J6, Pellecchia M6, Sarkar D5, Fisher PB7.

Show Affiliations

1Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.

2Institute of Life Sciences, Bhubaneswar, Orissa, India.

3The University of Jordan, Department of Biological Sciences, Amman, Jordan.

4Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia. VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.

5Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia. VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia. VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.

6Sanford-Burnham Medical Research Institute, La Jolla, California.

7Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia. VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia. VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia. [email protected]

Abstract

Improved treatments for pancreatic cancer remain a clinical imperative. Sabutoclax, a small-molecule BH3 mimetic, inhibits the function of antiapoptotic Bcl-2 proteins. Minocycline, a synthetic tetracycline, displays antitumor activity. Here, we offer evidence of the combinatorial antitumor potency of these agents in several preclinical models of pancreatic cancer. Sabutoclax induced growth arrest and apoptosis in pancreatic cancerells and synergized with minocycline to yield a robust mitochondria-mediated caspase-dependent cytotoxicity. This combinatorial property relied upon loss of phosphorylated Stat3 insofar as reintroduction of activated Stat3-rescued cells from toxicity. Tumor growth was inhibited potently in both immune-deficient and immune-competent models with evidence of extended survival. Overall, our results showed that the combination of sabutoclax and minocycline was highly cytotoxic to pancreatic cancer cells and safely efficacious in vivo.

©2015 American Association for Cancer Research.

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Pancreatic Cancer Combination Therapy Using a BH3 Mimetic and a Synthetic Tetracycline. Global Medical Discovery

 

 

 

 

 

 

 

 

 

 

 

 

About The Author

Bridget A. Quinn is an MD/PhD student at Virginia Commonwealth University School of Medicine in Richmond, VA.  She completed her PhD work in 2014 in the laboratory of Dr. Paul B. Fisher, Professor and Chairman in the Department of Human and Molecular Genetics and Director of the VCU Institute of Molecular Medicine, where she studied novel therapeutic strategies in pancreatic cancer.