Targeting Ras/Raf/MEK/Map Kinase
Neha Vapiwala, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: October 16, 2005
The Ras/Raf/MEK/Map kinase pathway is a group of cellular proteins that play a key role in cellular growth and proliferation. When a growth-stimulating hormone or growth factor binds to a receptor located on the cell's surface, a series of subsequent events take place within the cell. Specifically, the ras protein is activated and in turn activates raf. Raf then activates MEK, which is an activator of map kinases (ie: Erk) that ultimately trigger cell proliferation. This process, by which a message from outside the cell is delivered through the surface and into the cell, is referred to as receptor-mediated cell signaling. The ras signaling pathway is well-described, and has been implicated in regulation of cellular motility, invasiveness, and immortality, among other things. Mutations of proteins in this pathway have been found to contribute to about 20% of all human cancers. In fact, ras is the most frequently mutated known oncogene in human tumors. Ras mutations are present in about 90% of pancreatic adenocarcinomas, 50% of colon adenocarcinomas, and 40% of lung adenocarcinomas. B-raf oncogene mutations have been implicated in 68% of metastatic melanomas, 36% of papillary thyroid cancers, and a smaller but substantial percentage of colorectal and other solid tumors.
Farnesyltransferase Inhibitors (FTIs)
Several FTIs are in various stages of laboratory and clinical development, and appear to have broad activity against breast cancer cell lines. There appears to be enhancement of benefit (synergy) when FTIs are used together with cytotoxic agents.
Zarnestra (R115777, tipifarnib) is the FTI that is furthest along in development. A phase II trial of patients with previously treated metastatic breast cancer tested two different dosing schedules: continuous and intermittent. The objective response rates in the 2 groups were 10% and 14%, with an additional 15% and 9% who had stable disease for at least 6 months. The major side effects observed were bone marrow suppression and neuropathy, both of which were less in the intermittent dosing group than the continuous. Several phase I studies of zarnestra and other FTIs have been performed in combination with cytotoxic chemotherapy and have demonstrated the safety of these combo regimens. Phase II trials in breast cancer are underway, including one using zarnestra in combination with an aromatase inhibitor. FDA approval for zarnestra use in acute myeloid leukemia (AML) is pending phase III data, as the FDA committee voted against accelerated approval for zarnestra based on data from a single-armed phase II trial.
Sorafenib (BAY 43-9006) is the first compound to target not only the Raf/MEK/Erk signaling pathway (as mentioned above), but also the VEGFR and PDGFR pathways (see Targeting Angiogenesis section). It was first developed by Onyx Pharmaceuticals, which then partnered with Bayer in order to complete drug development. In March 2004, sorafenib was granted Fast Track status by the FDA for metastatic renal cell cancer. In April 2005, sorafenib was accepted into the Pilot 1 Program, which is designed for therapies that have been granted FDA Fast Track status and that have the potential to provide significant benefit over existing standard therapy. Bayer and Onyx are sponsoring numerous clinical trials to help catapult this drug into the forefront of anti-cancer targeted therapies.
There are several large, international, multiinstitution phase III clinical studies of sorafenib underway in patients with advanced stage primary cancers of the kidney and liver, as well as metastatic melanoma.
At this year's American Society of Clinical Oncology (ASCO) conference, results of a planned interim analysis of an ongoing phase III trial in patients with advanced kidney cancer were presented (Escudier et al.). Among 769 analyzed patients, progression-free survival (PFS) was doubled to a median value of 24 weeks with sorafenib, compared to 12 weeks with placebo. The benefits from sorafenib were observed in all patient subgroups, regardless of age, duration of disease, or prior therapies. Disease control was achieved in 80% of patients who received sorafenib: 78% had stable disease (compared to 55% in the placebo arm) and 2% had partial response (compared to none in the placebo arm). The 12-week progression-free rate was 79% for sorafenib vs. 50% for placebo. Furthermore, sorafenib was very well tolerated in 768 patients, and the most common side effects were hypertension, fatigue, diarrhea, and rash, including a rash on the hand and foot (hand and foot syndrome).
In light of these results, and based on discussions with the principal investigators, the DMC, and regulatory authorities, Bayer and Onyx recommended that all patients in this trial be offered access to sorafenib (i.e. switch out of the placebo arm). Also, Bayer and Onyx submitted a New Drug Application (NDA) for possible approval in this indication by the U.S. Food and Drug Administration (FDA).
Bayer and Onyx also recently announced the availability of sorafenib through an open-label, FDA-reviewed treatment protocol for eligible patients with advanced kidney cancer (Advanced Renal Cell Carcinoma Sorafenib study, or ARCCS).
Phase II efficacy trials are studying sorafenib as a single agent in advanced lung, breast, and other cancers.
Phase I/II clinical trials are investigating sorafenib in combination with a range of standard chemotherapeutics and other anticancer agents.
ISIS 5132 is another raf inhibitor that has shown acceptable toxicity in phase I studies. Phase II studies are now underway in a variety of cancer types.
CI-1040 is an oral, selective small-molecule inhibitor of MEK 1-2. Animal and culture studies have shown activity of this agent in breast cancer cell lines. Phase I studies have found mild gastrointestinal and skin side effects. Unfortunately, a phase II study in 67 patients with 4 different tumor types (advanced colorectal, NSCLC, breast, and pancreatic cancer) found no responses, although CI-1040 treatment was well tolerated.
PD 0325901, a second generation MEK inhibitor, has recently entered clinical development and appears to have noticeably better pharmacologic properties compared to CI-1040, which investigators hope may translate into better anti-cancer efficacy. It has shown some partial response in melanoma patients. The dose for phase II studies has not yet been determined.