Alert Number 302
Date: October 28, 2008
I know this is the season for politics. But I promise I am not talking about Iraq and Afghanistan. My politics are my own business and I recognize CLL is a non-discriminatory cancer.
A Two Front War
I am talking of something far more dangerous to our patient community, much more up-front and personal to us. I spent a lot of time in the last few days trying to help a good friend deal with the news of CLL and metastasized melanoma. As I looked around for possible therapy options and encouraging clinical trials that may be relevant to my friend, I was reminded once again how difficult this combination can be. Truly, fighting CLL and skin cancer is a two front war that no one would want to face.
Talking to the experts it became clear to me that when faced with this combination the melanoma takes center stage, CLL fades into the background. In fact, it was recommended that therapy targeting the CLL alone is perhaps not a good thing to do, since most CLL drugs reduce immune function, something that is badly needed for the body to control the melanoma to some degree.
My friend did find a good clinical trial at Ohio State that might well work for her. This melanoma clinical trial uses a combination of Velcade (technical name “bortezomib”) + interferon alpha. While there is no specific targeting of CLL in this clinical trial, what made it intriguing to me and my friend is that this combination may be useful in CLL as well! With any luck this would be a case of killing two birds with one stone. For those of you who may be interested, I have attached a PubMed abstract that talks about this combination. Let me know if you want to read the full length version of the article.
Velcade + IFN-alpha
Velcade is one of a class of cancer drugs called proteasome inhibitors. Here is a quick and dirty way of understanding how these drug works. Think of proteasomes as garbage trucks. They are important in hauling out the toxic waste produced by the cell as it goes about its business of living. If the garbage is not hauled out and properly disposed, the cell gets poisoned by its own waste products. What happens when proteosomes are inhibited from doing their job of garbage collection? Think of New York City during the hot summer months when the garbage guys go on strike and the ever so smelly garbage piles up along the streets. You get the picture. Now, remember this too. Cancer cells are notorious for producing lots of garbage. They are not like good and law-abiding citizens, putting their “green” politics into practice and producing as little garbage as possible. So, who do you think is more hurt by the garbage strike? You guessed it - proteasome inhibition hurts cancer cells a lot more than it hurts healthy cells, because they have more garbage to deal with. Anytime we have a drug that hurts cancer cells more than it hurts healthy cells, we have the potential for finding the right dose of the drug in the right protocol that kills only cancer cells while leaving healthy cells alone – what is called a good “therapeutic window”.
When Velcade was first introduced in 2003 it was the first important drug approved by the FDA in more than a decade for multiple myeloma. Velcade has also been in a few CLL studies, but the results have not been all that impressive. It has been suggested that while Velcade can destabilize the cancer cells (poison them with their own garbage), actual killing of the cancer cell requires an assist from the body’s own immune system. No wonder Velcade as a single agent was not all that successful in CLL patients. Once again we are reminded our dysfunctional immune systems are unable to deliver the killing blow to the CLL cells, even when they are Velcade poisoned.
That is what makes this combination of Velcade with Interferon alpha so interesting. There has been a lot of interest in IFN-alpha as an immune system boosting drug. The hope is that the combination of the one-two punch of Velcade poisoning along with IFN-alpha goosed immune system will do the job of killing cancer cells. It is particularly interesting that the abstract points out the combination may be useful in fighting melanoma cells that over express Mcl-1 and Bcl-2. Careful readers of our reviews will remember that both Bcl-2 and Mcl-1 are also markers of aggressive disease in CLL. Now you understand why I am hopeful this combination may be helpful in treating my friend with CLL and metastatic melanoma.
For those of you who have not yet faced life with skin cancer and would like to keep it that way, here is a very useful link to Mayo Clinic on the subject of skin cancer. How to recognize it, what to do etc. Notice that in the risk factors for skin cancer (beyond the usual fair skin, high UV exposure etc) Mayo points out people with weakened immune systems are at greater risk of developing skin cancer. This includes “people living with HIV/AIDS or leukemia and those taking immunosuppressant drugs after an organ transplant.”
Cancer Res. 2008 Oct 15;68(20):8351-60
IFN-alpha and bortezomib overcome Bcl-2 and Mcl-1 overexpression in melanoma cells by stimulating the extrinsic pathway of apoptosis.
Lesinski GB, Raig ET, Guenterberg K, Brown L, Go MR, Shah NN, Lewis A, Quimper M, Hade E, Young G, Chaudhury AR, Ladner KJ, Guttridge DC, Bouchard P, Carson WE 3rd.
Department of Internal Medicine, Division of Hematology and Oncology, The Ohio State University, Arthur G James Cancer Hospital and Richard . Solove Research Institute, Columbus, Ohio 43210, USA.
We hypothesized that IFN-alpha would enhance the apoptotic activity of bortezomib on melanoma cells. Combined treatment with bortezomib and IFN-alpha induced synergistic apoptosis in melanoma and other solid tumor cell lines. Apoptosis was associated with processing of procaspase-3, procaspase-7, procaspase-8, and procaspase-9 and with cleavage of Bid and poly(ADP-ribose) polymerase. Bortezomib plus IFN-alpha was effective at inducing apoptosis in melanoma cells that overexpressed Bcl-2 or Mcl-1, suggesting that this treatment combination can overcome mitochondrial pathways of cell survival and resistance to apoptosis. The proapoptotic effects of this treatment combination were abrogated by a caspase-8 inhibitor, led to increased association of Fas and FADD before the onset of cell death, and were significantly reduced in cells transfected with a dominant-negative FADD construct or small interfering RNA targeting Fas. These data suggest that bortezomib and IFN-alpha act through the extrinsic pathway of apoptosis via FADD-induced caspase-8 activation to initiate cell death. Finally, bortezomib and IFN-alpha displayed statistically significant antitumor activity compared with either agent alone in both the B16 murine model of melanoma and in athymic mice bearing human A375 xenografts. These data support the future clinical development of bortezomib and IFN-alpha for malignant melanoma.
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