1.Understanding side effects better in order to design a response or treatment strategy!
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There nothing annoying more the Oncologist and of course the cancer patient who is victimized than chemotherapy side effects. To me this is a experienced as a "let down" from sometimes a good drug. Here we are having a good response or even a stable disease, but the side effect pushes the treatment to a halt.
And quite frankly, current literature aside from listing the side effect, does not provide much in terms of why the side effect happened in the first place. And I understand it is difficult to say, but let it ride is not always the best option. It leaves in the mind of the Oncologist an unexplained "caveat". One of the thing driving medication prescription patterns is not only response to therapy based on phase II or III randomized studies, but rates of response to treatment and panoply and intensity of side effects of the drug. These factors determine the level of "comfort" with the drug. And with that level of comfort comes the "selling" of the drug to our patients who are the ultimate consumer.
The point is that deciphering the mechanisms underlying a side effect is not clear.
1-Is the side effect a direct effect from the drug
2.Is the side effect due to subsequently released cytokines
3.does patient have to have a deficiency in their genes (gene Heterozygosity ) to experience it
4.Is the side effect a bystander effect
etc...
At CRBCM, we are interested in deciphering the mechanism(s) of RASHES during the use Anti-EGFR and various Kinases. It is said that the worse the RASH the higher the response to Cetuximab and Tareceva for that matter. BUT THE WHY HAS BEEN LEFT FOR US TO GUESS!
DIARRHEA WITH CPT-11 OR THE ANTI-EGFR AND THE SUNITINIB (TKIs)
THE NEUROPATHY
----------------------.Now Neuropathy is an interesting one.!!
ie. post synaptic Neuron death during post Brain or nerve injury has been partly attributed to inflammatory Cytokines liberated in supportive glial cells. But we know that in Diabetics that obliteration of vasa vasorum or more clearly in (the nerve) small vessel feeding the nerve (vasa nervosa I am suggesting1) may play a role. There is no question in my mind that drugs such as the Taxanes will induce epigenetic consequences liberating some nocive Interleukins...
Bleeding from Avastin is an intriging one, somewhere I remember that an cofactor gene or anchor to the VEGF is affected. will sharpen my understanding again before delving further into this discussion.
Gene wise this is an interesting area since most of the target therapy since to share these side effect.
ONE OF THE INTRIGUING SET OF SIDE EFFECTS RESEARCH, IS THE DIFFERENCE OF IN THE PANOPLY OF SIDE EFFECTS BETWEEN AN ANTI-BRAF AGENT AND AN ANTI-MEK.
THE SLEW OF SIDE EFFECTS IS SIMILAR HOWEVER, THE ANTI-BRAF GIVES YOU A SURPRISING SIDE EFFECT. NOT ONLY IT GIVES YOU A DERMATITIS/RASH BUT IT PUSHES THE ENVELOP FURTHER TO GIVE YOU A SQUAMOUS CELL CANCER OF THE SKIN! AS IF NOW THE NF-kB IS INVOLVED? AS IF THE HSP 90 (OR IS-IT HSP 60 ) AND OF COURSE THE Wnt AND NOTCH? OR MAY BE REPAIR MECHANISMS OF SKIN DAMAGE CAN'T HANDLE THE CYTOKINES AFFECTING THE EPIDERMAL RECEPTORS? DAMAGE TO RECEPTORS? REALLY A TEASER WHEN IT COMES TO EXCITED RESEARCHERS!
2.WHICH ONE DOES WHAT?
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FDA approved anti JAK
-Tofacinib (anti JAK 1 and 3)
-Ruxolitinib (Anti JAK 1 and 2)
One of the reality in the cell, is the issue of Heterozygosity of genes which affect how we respond to drugs and stimuli, a fact clearly affecting our prognosis. But surprisingly, some form of genes give squarely the opposing effect! Basically we could be death or alive because the same gene has a minimal molecular change. (the story of Sickle cell comes running in my mind). Another interesting set of fact is that some cellular molecule belong to a "same family" but could play opposing role Interleukin 4 vs Interleukin-1 for example. And now the JAK, the Metalloproteases, the TGFs,the Interferons, the MUC gene,THE SRC, the STATs and it goes on and on. We need mapping of these things to design a strategy of Use.AND AS I USUALLY SAY, COMPUTER CAN HELP. LET'S FACE IT ONE MIND CANNOT DO WHAT A PC CAN!
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