Medical Inspiring Malignant Melanoma Phase I Clinical Trial Story: NY Times

[rhody]

http://www.nytimes.com/2010/02/23/health/research/23trial.html?pagewanted=1"

From New York, Dr. Paul B. Chapman of Memorial Sloan-Kettering Cancer Center, perhaps the most determined skeptic of the group, acknowledged, “This looks impressive.”

The trial of PLX4032 offers a glimpse at how doctors, patients and drug developers navigate a medical frontier as more drugs tailored to the genetic profile of a cancer are being widely tested on humans for the first time.

Throughout the fall, the only two patients on the trial whose tumors continued to grow were the ones who did not have the particular gene mutation for which the drug had been designed. They were removed from the trial. By late December, tumors in the 11 patients who did have the mutation had shrunk. Those involved in the trial held their collective breath waiting to see how long the remissions would last.

http://www.cancerhelp.org.uk/trials/types-of-trials/phase-1-2-3-and-4-trials"

Inspiring story, especially the one about Chris Nelson who was almost not eligible for the trial. Scroll down and watch the video.

Rhody...

 

[Monique]

There is a recent paper in Nature that gives more insight into the mechanism of action of the drug: http://www.nature.com/nature/journal/vnfv/ncurrent/pdf/nature08902.pdf".

Tumours with mutant BRAF are dependent on the RAF–MEK–ERK signalling pathway for their growth1–3. We found that ATP-competitive RAF inhibitors inhibit ERK signalling in cells with mutant BRAF, but unexpectedly enhance signalling in cells with wild-type BRAF. Here wedemonstrate the mechanistic basis for these findings. We used chemical genetic methods to show that drugmediated transactivation of RAF dimers is responsible for paradoxical activation of the enzyme by inhibitors. Induction of ERK signalling requires direct binding of the drug to the ATP-binding site of one kinase of the dimer and is dependent on RAS activity. Drug binding to one member of RAF homodimers (CRAF–CRAF) or heterodimers (CRAF–BRAF) inhibits one protomer, but results in transactivationof the drug-free protomer. InBRAF(V600E) tumours, RAS is not activated, thus transactivation is minimal and ERK signalling is inhibited in cells exposed to RAF inhibitors. These results indicate that RAF inhibitors will be effective in tumours in which BRAF is mutated. Furthermore, because RAF inhibitors do not inhibit ERK signalling in other cells, the model predicts that they would have a higher therapeutic index and greater antitumour activity than mitogen-activated protein kinase (MEK) inhibitors, but could also cause toxicity due to MEK/ERK activation. These predictions have been borne out in a recent clinical trial of the RAF inhibitor PLX4032 (refs 4, 5). The model indicates that promotion of RAF dimerization by elevation ofwild-typeRAFexpression orRASactivity could lead to drug resistance in mutant BRAF tumours. In agreement with this prediction, RAF inhibitors do not inhibit ERK signalling in cells that coexpress BRAF(V600E) and mutant RAS.

In short tumors with mutated BRAF are dependent on the RAF–MEK–ERK pathway. The inhibitor works by inhibiting RAF. Previous clinical trials have been done by inhibiting MEK, but treatment is limited due to toxicity. Surprisingly inhibition of RAF by the compound does not lead to reduced levels of MEK in wild-type cells, but even higher levels (due to drug-mediated transactivation of RAF dimers). This allows for the administration of a high dose of the inhibitor and a stronger inhibition of the ERK pathway in the BRAF-mutated tumor cells. Drug resistance does develop, due to activating mutations in BRAF, RAS or RAF.

I'm curious about the follow-up clinical studies with this new compound.

There are other studies that target specifically the melanin pathway, where the zebrafish is used as a model organism. They specifically could eliminate the melanoma and other melanin-producing cells, but I wonder what the side-effects would be in humans (albinism?).