Identification of Low-Dose Multidrug Combinations for Sunitinib-Naive and Pre-Treated Renal Cell Carcinoma - Beyond the Abstract

Clear cell renal cell carcinoma (ccRCC) accounts for 70% of all kidney cancers and causes the highest mortality among urological diseases. Its nature to be or become resistant to radio-, chemo- and targeted drug therapy remains an unsolved problem. Therefore, to overcome those challenges, combined treatment strategies are currently under development.

Our latest research focusses on the development of optimized multidrug combinations (ODC) specific to human ccRCC subtypes. Those ODCs holding numerous advantages, such as (i) administration at low doses, (ii) occurrence of fewer side-effects, (iii) ability to repurpose known drugs, (iv) reduction of induced treatment resistance, (v) elimination of pre-existing treatment resistance.

In our in vitro studies, using biological assays and statistical tools, we optimized multidrug combinations consisting of a cocktail of four drugs applied concomitantly that are highly active and safe at the same time. These multidrug combinations were optimized to reduce the viability of sunitinib (Sutentâ„¢)-sensitive and sunitinib-resistant ccRCC cells. Sunitinib represents one of the first-line treatment options in clinical use. We observed that in response to the ODC treatment, the morphology of cancer cells changes, i.e. cell-to-cell connections promoting treatment resistance rupture, and cell proliferation are arrested. Targeting the cancer cell from more than one angle, by applying four drugs simultaneously, enables to kill the cancer cells actively while overcoming multi-drug resistance and prevent the quick induction of new treatment resistance. It is important to note that the power of four-drug combinations in overcoming treatment resistance has already been proven in the field of bacteriology and oncology and others. Treatment with these optimized multidrug combinations induced cell death and was more effective as compared to the current standard-of-care applied in the clinic.

In this case, the multi-drug combinations can be augmented in an individualized fashion to enhance the treatment success and to prolong the overall survival of each patient. Further mechanistic studies and preclinical validation is now necessary to study and evaluate the potential of those optimized multidrug combinations for future clinical use.

Written by: Magdalena Rausch, Andrea Weiss, Joanna Achkhanian, Andrei Rotari, Patrycja Nowak-Sliwinska

Molecular Pharmacology Group, Institute of Pharmaceutical Sciences of Western Switzerland, 1 Rue Michel-Servet, 1211, Geneva 4, Switzerland., Molecular Pharmacology Group, Institute of Pharmaceutical Sciences of Western Switzerland, 1 Rue Michel-Servet, 1211, Geneva 4, Switzerland. .

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