Rational Design of a Therapeutic Program for Multiple Myeloma Using a Strategy of Drug Repurposing and Combination Therapy

The extremely long development time and low success rate for new drug development programs has translated into limited clinical options in the treatment of cancer. The challenge is further compounded by drug resistance seen in clinical settings for approved standard of care therapeutic options like chemotherapy and targeted drugs like Bortezomib in Multiple Myeloma (MM). This has accelerated the need for initiatives and strategies which promote innovation but drastically reduce drug development failures through prediction of clinical outcomes. We present here a methodology and rationally designed therapeutic program for MM. This program has novel first-in-class mechanism of action and has been developed using a strategy of re-purposing and combinations based on National Center for Advanced Translational Sciences (NCATS) library of industry-provided drugs.

The therapy design and development was completed using validated proprietary technology from Cellworks which enables simulation of cancer disease physiology computationally for predicting clinical outcomes. The comprehensive integrated representation of signaling and metabolic networks across all disease phenotypes and functional proteomics abstraction facilitated a large number of predictive studies in weeks with quantitative transparency into the network. The predictive cancer technology was customized to four MM profiles: OPM2, RPM1, SKMM2 and U266. Ten of the molecularly targeted drugs from the NCATS library were digitally screened alone and in combinations of two across the four MM profiles at four concentrations (C, C/2, C/4, and C/8). Based on screening of over six thousand predictive studies, three designed therapeutics hits were intelligently shortlisted based on synergistic impact on viability and proliferation.

The focused therapeutic candidate hit was selected based on synergy using viability endpoints and apoptosis markers such as caspase 3, PARP1 at sub-therapeutic doses. The proposed therapeutic regimen is a sub-therapeutic combination of AT101 and AVE0847. AT101 is a BCL2 inhibitor and AVE0847 is a PPAR alpha and gamma agonist agent. The concentration of each drug used in the designed therapy was close to IC30. The predictive results showed a synergistic increase in apoptotic markers caspase 3 and PARP1 cleaved form. This hit candidate is being pre-clinically validated experimentally across four MM profiles and results will be presented.

The design of first in class mechanism of action based therapeutic strategies of drug rescue/repurposing has been used to identify AT101 and AVE0847 as a promising drug combination for use in MM which predicatively results in a synergistic increase in apoptosis. These results are currently being validated in vitro. The inherent multi target mechanism of action predicted by this combination could potentially eliminate the drug resistance challenges of single target therapeutics.

No relevant conflicts of interest to declare.