I have decided to keep my cold, which I no longer see as a nuisance. Hurray for cold viruses! Ok, ok, I am being a tad (!) facetious. 🙂 Seriously, now. Yesterday morning, by chance, while looking up the most recent news on parthenolide online (nothing new to report since my October 3 post, by the way), I came across an interesting website, Cancer Research UK (http://tinyurl.com/2xh2wc). Its list of articles included one with my blog title, i.e., Modified Cold Virus May Kill Cancer Cells. Hmmm, intriguing title, I thought, so I clicked on the link and read that researchers from Birmingham University have developed a genetically modified form of the cold virus, a form that will not replicate (i.e., it won’t make us cough or sneeze) but merely serves as a vehicle to transport a human protein called CD40L to a cancer cell. Here it sticks to another protein, called CD40, which is present on the surface of many types of cancer cells (breast, liver and skin cancer, to mention a few). And the result of this sticky business? Apoptosis!
I could have stopped at that, but no, I just had to see if CD40 is present on the surface of myeloma cells. It is. So I dug deeper. Mamma mia! What a headache. I admit that I find myself more than a bit overwhelmed after being fully immersed in molecular science research for the past 36+ hours. So many studies, so much virtually incomprehensible technical lingo, so little time (and desire!) to earn a degree in biology and chemistry! 😉 I have now come to doubt that this “cold vehicle could be useful to myeloma patients (see below). In fact, this morning I almost threw away all my research and writing, but, to be honest, the CD40 topic was interesting, and the targeting of this protein may be relevant in the near future conventional treatment of myeloma, so I edited out some of the more convoluted stuff and decided to give the topic a quick whirl.
CD40 is an interesting molecule. It is present, at low levels, also on the surface of healthy cells, for instance of B cells (immune system cells). Under normal circumstances, I read, it is supposed to defend us from the attacks of viruses, bacteria and harmful substances and can even provoke apoptosis in tumour cells. However, it does not always perform as well as it should, which can be a big problem. In order to become activated, it needs to bind with its ligand, which I found also endearingly described as its soulmate, i.e., the above-mentioned CD40L (“L” stands for “ligand,” by the way), also known as CD154. So, as I understand it, the modified cold virus acts like a little Cupid reuniting two passionate lovers that are lethal to certain types of cancer cells. The embrace between CD40 and its ligand, in fact, sets off a cascade of events that eventually lead to the death of these particular malignant cells.
I should note that a body’s immune system becomes activated during this process. Now, a blog reader recently brought up the point that the immune systems of myeloma patients are already over-stimulated and should not be stimulated any further. I have read warnings to that effect here and there on Internet but have to confess that it is not a theme that I have researched thoroughly. I recognize that it is an important topic, though, so it will be added on my to-be-researched-in-a-hurry list.
CD40 and myeloma studies. There are heaps of ’em. I will discuss only a few of all the studies I have gone through since yesterday. A 2002 Dana Farber study published in Blood (see full text: http://tinyurl.com/249aog) tells us that CD40 induces MM cell migration and vascular endothelial growth factor (VEGF) secretion, suggesting a functional role of CD40 activation in MM homing and angiogenesis. This functional role is bad news for us, of course. When CD40 is activated, the researchers suggest, the result is tumour progression. CD40 also activates the infamous NF-kappaB, which, as we know, protects myeloma cells from death, via different mechanisms. In essence, CD40 appears to be involved in the proliferation of myeloma cells, so the authors suggest that targeting this pathway may prevent multiple myeloma from progressing. Interesting.
This had already been suggested back in 1995, again by a Dana Farber team (http://tinyurl.com/3b983v). Here are a few relevant excerpts from the 1995 “Blood” study: MM cells can be triggered via CD40L to secrete IL-6, suggesting the possibility for induction of IL-6-mediated autocrine MM cell growth. [ ] CD40L-CD40 interactions between MM cells, or between MM and BMSCs may be implicated in triggering IL-6 secretion and result in both paracrine and autocrine IL-6-mediated tumor cell proliferation. This study stopped me from looking fondly upon the modified cold virus theory. I am not sure what these “interactions” are, but perhaps it is not a good idea to put these two proteins together in the case of myeloma, unless I have totally missed the point or unless things have changed in the past 12 years, which is more than possible. The study ends: Further elucidation of the in vivo role of CD40-CD40L interactions between MM cells and cells within the marrow microenvironment may, not only elucidate the mechanisms of IL-6-mediated tumor cell growth, but also offer innovative therapeutic strategies. Indeed! The jury is still out.
Targeting CD40. Another Dana Farber study (full study: http://tinyurl.com/2fa4t5) published in 2005 discusses an anti-CD40 monoclonal antibody tested against multiple myeloma cells. This antibody, CHIR-12.12, apparently can inhibit multiple myeloma cell growth in the bone marrow milieu. I don’t need to underline the importance of THAT sentence! Two Phase I clinical trials are currently investigating the anti-CD40 theory in multiple myeloma. One is testing an anti-CD40 monoclonal antibody called SGN-40 (Anti-huCD40 mAb) on refractory or recurrent multiple myeloma (see: http://tinyurl.com/ysahre), in various medical centres throughout the U.S. This 2005 abstract provides information about SGN-40 and the above-mentioned trial: http://tinyurl.com/2wd567. SGN-40 apparently inhibits malignant cell growth by both antibody-induced cell death (AICD) and antibody-dependent cell-mediated cytotoxicity (ADCC). The other trial (http://tinyurl.com/2easoj) is testing HCD122, another anti-CD40 monoclonal antibody, on relapsed or non-respondent myeloma patients.
Speaking of clinical trials, the Birmingham researchers are in the process of developing skin and liver cancer clinical trials to test the above-discussed modified cold virus technique. I admit that I find all of these studies interesting, even though molecular science and fiddling around with genes is not my cup of chocolate and curcumin 😉 , and I doubt I would ever participate in an anti-CD40 myeloma clinical trial. But hey, the thought that curcumin or one of the other non toxic substances in my protocol might already target this protein just popped into my head. More research…tomorrow.