[Coastal Eddy]

Metformin + ritonavir appears very effective in myeloma

by Coastal Eddy on Wed Jul 08, 2015 2:39 pm

A combination of two approved drugs with extensive safety and toxicity data has shown dramatic effects on multiple myeloma. The attached Medline abstract below for the Dalva-Aydemir article describes the potential very high efficacy of combined already approved drugs ritonavir and metformin in selectively killing multiple myeloma. They mention in the last few paragraphs of the Discussion section that currently administered doses of both drugs corresponding to their study have already been used in patients (not MM-only patients - but multiple myeloma patients with diabetes patients with HIV). The combination is well tolerated.

The good news is the City of Hope (COH) is planning a clinical trial of combined metformin / ritonavir. The plan is being submitted to their IRB (Internal Review Board) for approval. One of the co-authors of the Dalva-Aydemir 2014 "Targeting Glycolysis & Compensatory Mito­chon­drial Metabolism In Multiple Myeloma" journal article I mentioned here in the forum is now a key clinician at COH (Dr. Rosen). I will paste in the Medline abstract of this article below.

If this works as hoped for, the total monthly cost of metformin (about $3) plus ritonavir would be about $300 in the US, or less than $60 outside the US (due to ritonavir pricing difference). Generic ritonavir may be available as early as next year, dropping the cost even further.

The scientific considerations regarding the mechanism of inducing apoptosis (killing) of multiple myeloma cells seems sound and the substantial amount of safety and toxicity data from multiple myeloma patients with HIV using this drug combo is very encouraging. Please help get the word out. Their may also be interest in conducting a similar metformin / ritonavir trial at UCSD Moores Cancer Center as well. Perhaps Abbvie Pharma (former Abbott Labs) the innovator company that created ritonavir would be interested in funding an extension to the current approved indication to include multiple myeloma.

Sevim Dalva-Aydemir et al, "Targeting Glycolysis and Compensatory Mitochondrial Metabolism In An In Vivo Xenograft Model Of Multiple Myeloma With FDA Approved Ritonavir and Metformin", ASH 2013 Annual Meeting Abstract 1922 (Poster Presentation)

Abstract:

Introduction: Multiple Myeloma (multiple myeloma) is an incurable plasma cell malignancy accounting for 11,000 deaths annually in the US and 20% of deaths from all hematological malignancies. multiple myeloma is one of myriad malignancies exhibiting enhanced glucose consumption associated with an aerobic glycolytic phenotype (i.e. the Warburg effect). We have previously published a study defining key glucose transporters responsible for facilitating glucose entry in myeloma and observed that multiple myeloma cells rely on constitutively cell surface-localized GLUT4 for basal glucose consumption. multiple myeloma cells cultured in the absence of glucose or upon GLUT4 suppression exhibit either overt apoptosis (sensitive phenotype) or growth arrest (resistant phenotype). To further demonstrate the clinical utility of targeting GLUT4 for multiple myeloma therapy we tested a HIV protease inhibitor ritonavir that has an off-target inhibitory effect on GLUT4. Treatment of multiple myeloma cells with physiologically achievable concentrations of ritonavir blocks glucose entry resulting in multiple myeloma cell death or growth suppression. To determine ritonavir’s specificity in targeting GLUT4 we generated KMS11 myeloma cell lines over-expressing GLUT1. As anticipated, in in vitro studies GLUT1 overexpressing cells were found to be resistant to ritonavir. multiple myeloma cells that were resistant to glucose-deprivation were further sensitized when co-treated with metformin, that we believe targets compensatory mitochondrial complex I activity. The objective of this study was to determine the in vivoefficacy of combinatorial ritonavir, metformin or the combination using the KMS11-GLUT1 or GFP (green fluorescent protein, as a negative control) expressing cells in a xenograft model of multiple myeloma.

Methods: KMS11 myeloma cells expressing GFP or GLUT1 were generated as previously described (Multiple myeloma exhibits novel dependence on GLUT4, GLUT8, and GLUT11: implications for glucose transporter-directed therapy. McBrayer SK, Cheng JC, Singhal S, Krett NL, Rosen ST, Shanmugam M. Blood. 2012 May 17;119(20)). NOD SCID mice were injected subcutaneously with KMS11-GFP or GLUT1 cells on the left or right side, respectively. When tumors were approximately 125 mm3, ritonavir 50 mgs/kg by oral gavage or metformin (125 mgs/kg) by i.p. injection or the combination were administered daily. Tumor volumes, weight, survival, glucose uptake and analysis of specific proteins in tumor lysates were performed.

Results and Conclusions: We first evaluated the impact of ritonavir/metformin or the combination on the viability of KMS11-GFP or GLUT1 expressing cells. Ritonavir elicits apoptosis in KMS11-GFP cells and less so in GLUT1 over-expressing cells, as anticipated (McBrayer S et.al Blood 2012). In vivo, however GLUT1 expressing cells were found to be highly sensitive to ritonavir while the parental GFP expressing cells were resistant. We have previously determined that cells resistant to glucose deprivation-elicited apoptosis have increased oxygen consumption and mitochondrial metabolism that can be targeted with metformin. Therefore, in order to target potential upregulation of mitochondrial OXPHOS we tested the complex 1 inhibitor metformin. We hypothesized that the KMS11-GFP cells in vivo were insensitive to ritonavir due to increased engagement of mitochondrial OXPHOS. In vitro studies with ritonavir and metformin demonstrate potent elicitation of apoptosis correlating with a loss of oxygen consumption and coupled respiration. Indeed, the administration of ritonavir with metformin elicits potent toxicity in both cell types in vivo. An investigation of cellular signaling pathways engaged in vivo indicates that ritonavir in combination with metformin suppresses AKT and AMPK activity and suppresses expression of pro-survival BCL-2 family member MCL-1. We have also demonstrated the efficacy of this treatment regimen in CLL primary patient samples and DLBCL and mantle cell lymphoma and other multiple myeloma cell lines. HIV patients chronically treated with ritonavir who exhibit diabetic symptoms have been treated with metformin indicating this combination treatment is well tolerated in humans (Kohli, R., et.al 2007. A randomized placebo-controlled trial of metformin for the treatment of HIV lipodystrophy. HIV Med 8:420-426). Our studies reveal a potent combinatorial regimen involving repurposed, FDA approved, ritonavir and metformin for the treatment of multiple myeloma and potentially other glucose-driven malignancies.

[Cheryl G]

Re: Metformin + ritonavir appears very effective in myeloma

by Cheryl G on Wed Jul 08, 2015 4:29 pm

Hello Eddy,

Thanks for your posting, and welcome to the forum.

While the research you've described certainly looks promising, I think it's worth emphasizing that this is a preclinical study involving rats implanted with two different myeloma cell lines. The rats were then treated with the two drugs you've mentioned.

Preclinical research with animal models is certainly more attractive than preclinical research that just looks at the impact of a potential treatment on myeloma cells in a petri dish. But the fact of the matter is that this is still just preclinical research.

As I suspect you already know, there have been many, many potential myeloma therapies that have shown significant anti-myeloma activity in preclinical studies, but which have been either ineffective, or just mildly effective, when tested in clinical studies with myeloma patients.

So, while I would not be surprised if the two-drug combination in this study shows show some efficacy when tested in patients, I'd say it's misleading to say these preclinical results demonstrate the combination is "very effective" as a myeloma therapy.

I'd also add that the 2014 journal article you mention in your other posting appears to basically include the research described in the ASH abstract you quote above. From what I can see, the two studies are not independent of one another. (ASH abstracts often lead to journal articles that flesh out in more detail what was summarized in the ASH presentation.)

I hope this drug combination does, in fact, prove effective in clinical trials. I just don't want anyone here misled into thinking that this study unequivocally demonstrates that we have a new myeloma therapy at hand.