Earlier this week, Danny Parker posted some compelling evidence that a drug commonly used to help control blood sugar in diabetics, metformin, may possess significant anti-myeloma properties. But could it work even better when combined with other drugs?
Here’s Danny’s next installment:
Metformin and Ritonavir as Potential Therapeutic Agents?
As we described last time, there is some evidence (albeit inconclusive) that metformin may slow progression of MGUS and myeloma with conventionally used agents such as Dexamethasone and Bortezomib (Velcade). However, there is also intriguing data over the last years showing that metformin when matched with another drug, ritonavir, routinely used to treat HIV, may have beneficial anti-myeloma impacts.
And the research paper describing the rationale for the trials:
And more recently, Dalva-Adyemiret al. (2015) – with Rosen one of the authors– again showed research suggesting possible effectiveness of ritonavir and metformin along with strong justification for its mode of action.
Ritonavir capitalizes on a key myeloma plasma cell malignancy characteristic: that of elevated glucose utilization which is intrinsic to the survival and proliferation of myeloma cells. Many myeloma patients who have had a PET (positron emission tomography) scan are aware that radioactive glucose is used in the test as the plasma cells have an elevated glucose uptake and may then become visible to sensitive whole body scans for concentrations of radioactivity.
But unlike healthy cells, myeloma cells depend strongly on certain types of glucose uptake mechanisms. Myeloma researchers have determined that myeloma clones depend heavily on glucose transporter-4 (GLUT4) for supporting their gluttonous glucose habit. This is where FDA approved protease inhibitor ritonavir comes in: it elicits a selective inhibitory effect on GLUT4. Metformin, on the other hand, inhibits mitochondrial complex 1 which GLUT4 impaired plasma cells seek to exploit to survive in the presence of ritonavir. When subjected to both therapies in combination, the hope is that myeloma cells will be killed outright (apoptosis) or otherwise severely inhibited. The combination of metformin and ritonavir becomes a sort of 1-2 punch to starve myeloma from its preferred mode of unrestrained replication.
Dr. Rosen has moved to the City of Hope and the clinical trial of metformin and ritonavir under Dr. Nitya Nathwani is scheduled to begin soon:
I will keep you posted as we learn more.
More from Danny early next week. I tried to help Pattie put up Christmas lights today, but this cold is kicking my butt! Nights are the worst. I tried drugging myself up with Nyquil last night. It made me groggy, but I was coughing so much it was hard to sleep. This is when we need a recliner; to try and sleep sitting up.
I’ve got a week to recover before ASH. So far my fledgling immune system seems to be engaging the bug. Let’s just hope it starts winning.
Feel good and keep smiling! Pat