Ovarian Cancer

*Researchers who conducted the study who conducted the use of Selumetinib in low grade serous Ovarian cancer were still puzzled because its activity did not follow presence of KRAS or BRAF. They have been wondering if it used another pathway.  But remember MEK is the revolving door to de-differentiation and to the reversal of mesengialization and as such increase tor susceptibility not only to chemotherapy drugs, but also to the secondary angiogenic potentiation of MEK.  That is, with anti-MEK, there is a down regulation of MAPK (as suggested) and therefore  the C-JUN and TGF and cyclins, but also down regulation of the VEGF!

They say " Our results suggest that selumetinib is an active agent, but not necessarily because of BRAF or KRAS mutational activation per se,” the authors concluded.

In an interview, Gershenson said that one reason for the lack of correlation could be biomarker instability. Among the 52 patients, specimens were available for only 40, mutational analysis was done in 34, and in 28 of those the tissue was from the primary therapy and not from the recurrent tumor. “The question arises, are these biomarkers stable over time or do they change, so that what you find in the primary tumor may not be what you find in the recurrent tumor,” he said."   They suggesting here that the lack of correlation could be due to a changing nature of Biomarker.  But the existence of other factors and pathways could not be be excluded!

Gene-Expression Profiling May Help Select Best Drugs for Pancreatic Cancer

Caroline Helwick 

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In this study patient with pancreatic cancer had reportedly circulating cell and their genes could predict response to therapy but unfortunately they did not spell out which genes were reviewed.  We will investigate further this article...

Fresh from ONCOFACTS

Low Grade Serous Ovarian Cancers Respond to Selumetinib
The GOG is conducting a phase II study of low grade serous ovarian cancers, which when recurrent are usually resistant to both hormonal therapy and chemotherapy. Patients with low grade serous ovarian cancer received selumetinib, an oral small molecule inhibitor of MEK 1 and 2, part of the MAP-Kinase pathway.
Of 52 patients treated with selumetinib, all had had at least one prior systemic therapy and 15% achieved a PR while 65% maintained Stable Disease. Median PFS was 11 months and two year OS was 55%.
While 14 patients had KRAS mutations and 2 had BRAF mutations, there did not appear to be any correlation between mutation status and response. A larger phase II-III clinical trial is beginning.

A PEEK INTO THE FUTURE!

The article published in the Lancet about Taxotere combined to Selumetinib in 2nd line treatment of lung cancer, opens the door to future therapy to come.  It marks the increasing trend of incorporating Target therapy to standard good old chemotherapy.  Selumetinib is a MEK inhibitor downstream from KRAS.
Already the results are impressive with the doubling of progression free survival and Overall survival.
Already, we have a peek to a new set of toxicity because these are new combinations and the outlook is grim now with almost half of the patients having Nausea, diarrhea, severe Neutropenia and stomatitis.
Not only is MEK down stream from RAS-RAF-MEK-ERK (MAPK) signaling pathway; it is the revolving door between epidermal presentation which should block Metastatic spread and Endodermal transformation that the Cancer chooses to metastasize.
Another question that will rise immediately is if we have a driver mutation, when should we stop inhibiting such target, when do we stop closing this revolving door? The rising need of maintenance therapy follows.  In lung cancer, Alimta, Tarceva and Taxotere have all shown to be beneficial in maintenance setting.  So the choice here would be Taxotere maintenance, or should we continue to push closed MEK with Selumetinib?
This article emphasized the fact that this was the first time that KRAS was used as a biomarker for  Target therapy.  Very true, but mesenchymal transformation and angiogenesis play a role in almost every cancer.
THE FIGHT IS ON.

(LAST POINT: WE HAVE NOT LEARNED ENOUGH ABOUT HOW TO PREVENT THESE SIDE EFFECTS, WE NEED TO STEP UP!)