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

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.