myeloma

Who knew? HIV and diabetes drugs cause myeloma cells to self destruct

Post in Inspirational Research

Sometimes medicines created to fix one thing end up working for something else, too.  I’m fascinated by the prospects that existing drugs–most likely used in unexpected combinations–may work against multiple myeloma, help us live longer.   Here’s an example.

Apparently the HIV drug, ritonavir, and diabetes drug, metformin, are toxic to myeloma cells.  Will the accidental breakthrough translate to patients?  Check out this abstract just published in the Journal of Clinical Cancer Research:

Targeting the Metabolic Plasticity of Multiple Myeloma with FDA Approved Ritonavir and Metformin

1. Sevim Dalva-Aydemir1,
2. Richa Bajpai2,
3. Maylyn Martinez3,
4. Kehinde U.A Adekola1,
5. Irawati K Kandela4,
6. Changyong Wei5,
7. Seema Singhal6,
8. Jennifer E Koblinski7,
9. Noopur S Raje8,
10. Steven T. Rosen9, and
11. Mala Shanmugam2,*

Author Affiliations
1. 1R.H. Lurie Comprehensive Cancer Center, Northwestern University,
2. 2Winship Cancer Institute, School of Medicine, Emory University
3. 3Feinberg School of Medicine, Northwestern University
4. 4Chemistry of Life Processes Institute, Northwestern University
5. 5Dept. of Hematology and Medical Oncology, Winship Cancer Institute, Emory University
6. 6Robert H. Lurie Cancer Center, Northwestern University
7. 7R.H. Lurie Comprehensive Cancer Center, Northwestern University
8. 8POB 217, Hematology/Oncology, Massachusetts General Hospital Cancer Center
9. 9Clinical Cancer Center, Robert H. Lurie Comprehensive Cancer Center of Northwestern University
1. ↵* Corresponding Author:
Mala Shanmugam, Winship Cancer Institute, School of Medicine, Emory University, 1365C Clifton Rd, Suite 4002, Atlanta, GA, 30322, United States mala.shan@emory.edu

Abstract
Purpose: We have previously demonstrated that ritonavir targeting of glycolysis is growth inhibitory and cytotoxic in a subset of MM cells. In this study our objective was to investigate the metabolic basis of resistance to ritonavir and to determine the utility of co-treatment with the mitochondrial complex I inhibitor metformin to target compensatory metabolism. Experimental Design: We determined combination indices for ritonavir and metformin, impact on myeloma cell lines, patient samples and myeloma xenograft growth. Additional evaluation in breast, melanoma, and ovarian cancer cell lines was also performed. Signaling connected to suppression of the pro-survival BCL2 family member MCL-1 was evaluated in MM cell lines and tumor lysates. Reliance on oxidative metabolism was determined by evaluation of oxygen consumption and dependence on glutamine was assessed by estimation of viability upon metabolite withdrawal in the context of specific metabolic perturbations. Results: Ritonavir-treated MM cells exhibited increased reliance on glutamine metabolism. Ritonavir sensitized MM cells to metformin, effectively eliciting cytotoxicity both in vitro and in an in vivo xenograft model of MM and in breast, ovarian and melanoma cancer cell lines. Ritonavir and metformin effectively suppressed AKT and mTORC1 phosphorylation and pro-survival BCL-2 family member MCL-1 expression in MM cell lines in vitro and in vivo. Conclusions: FDA-approved ritonavir and metformin effectively target MM cell metabolism to elicit cytotoxicity in MM. Our studies warrant further investigation into repurposing ritonavir and metformin to target the metabolic plasticity of myeloma to more broadly target myeloma heterogeneity and prevent the re-emergence of chemo-resistant aggressive MM.

• Received April 29, 2014.
• Revision received November 10, 2014.
• Accepted December 11, 2014.

Copyright © 2014, American Association for Cancer Research.

I call this the “Throw enough at the wall that something’s bound to stick.” theory.  Powerful computers are helping researchers match up the next best possible drug combinations.  That helps save a lot of time.  But sometimes blind luck gets the credit.  Did you know that the positive development of administering Velcade sub-q was a mistake?

That’s right.  A nurse in Europe began erroneously giving her patients Velcade by injection instead of IV.  It didn’t take long for her and her patients to notice a significant reduction in peripheral neuropathy.  How fortuitous!

The new Mayo Clinic measles therapy is another example.  Doctors discovered that myeloma patients who contracted measles experienced a dramatic drop in their numbers.  It’s taken almost a decade, but researchers may have finally figured out how to apply the breakthrough effectively.

Will ritonavir and/or metformin change the face of myeloma therapy?  Probably not.  But using them in a way scientists have yet to identify may help.  This feeds into my supposition that the cure for multiple myeloma is sitting on a researchers desk, buried  under a pile of folders and an unwashed coffee cup.  Odds say I’m right!