BVD-523

Cancer Approaches Yesterday, Today, and Tomorrow
Cancer cells are often quite sensitive to poisons, which explains why broadly toxic drugs are the oldest and most commonly used cancer drugs. Today, though, many cancer drugs exploit cell sensitivities caused by genetic mutations that are found only in cancers, but not in healthy tissue. BioMed Valley Discoveries is testing whether BVD-523 (ulixertinib), a novel targeted cytotoxic designed to inhibit ERK kinase, can be used to treat cancers that harbor mutations in the MAPK signaling pathway, making them highly reliant on ERK for survival and growth.

Within the past ten years, “targeted” cancer therapies have shown exciting promise. For example, a common mutation found in chronic myelogenous leukemia produces the BCR-ABL oncogene, and direct inhibition of this gene product using the kinase inhibitor drug imatinib/GleevecTM provides significant benefit to patients. Similarly, drugs have been approved that target a variety of cellular processes including proteins that affect cell proliferation, regulate gene expression, induce apoptosis, support tumor angiogenesis, are immunomodulatory as well as those that specifically deliver toxic molecules to cancer cells. Collectively, more than 30 drugs are approved or being evaluated in clinical trials that could be called targeted therapies. Clearly, cancer therapies with improved efficacy and reduced toxicity can be found by targeting molecular and cellular changes that are specific for cancer.

Cancer-specific changes often occur in the mitogen-activated protein kinase, or MAPK, pathway (see below). The MAPK pathway translates external signals outside of a cell into key decisions that affect cell growth. Once cell sensors detect external growth factors, the MAPK pathway acts inside the cell to translate those growth signals into increased cell survival, cell division, and cell movement. The MAPK circuit looks largely like a direct linear relay: RAS family GTPases turned “on” by growth signals go on to activate RAF family kinases, which then, in turn, activate MEK and ERK family kinases. ERK kinase, the final signal kinase of the MAPK pathway, activates effectors that directly encourage cell-cycle progression, motility, and differentiation while discouraging apoptosis.

 

WT MAPK signaling in melanoma

 

Cancers survive, grow and invade while ignoring whether growth factors are present--not surprisingly, cancers frequently reveal a MAPK circuit that looks as though it is “always-on." In fact, many cancers show frequent genetic mutations in MAPK components that “lock” the circuit in a pro-growth state, even in the absence of external growth signals. The MAPK pathway protein kinase BRAF exhibits auto-activating mutations in over half of cases of thyroid and melanoma cancers. More recent genetic studies suggest all but ~5% of melanomas may have a MAPK pathway that is “always-on” (see below), due to an array of mutations specific to this cancer. Beyond melanoma, the RAS GTPase is a classical cancer oncogene, which has been known for some time to be mutated in subsets of colon and lung cancers, as well as the majority of pancreatic tumors.

Targeted cancer drugs have been designed to turn off MAPK signaling, and the drugs are effective in melanomas where the MAPK circuit is “always-on” (see below). The BRAF inhibitor vemurafenib/Zelboraf provides substantial clinical benefit for some melanoma patients, causing both tumor regressions and improvements in overall survival. Vemurafenib is FDA approved as safe and effective, but only for patients where BRAF has undergone mutations that auto-activate MAPK signaling. This proves melanomas become addicted to “always-on” BRAF, and that drugs that turn off aberrant MAPK signaling can be effective cancer treatments.

 

BRAF signaling in melanoma

 

Still, targeted cancer therapies are not perfect, and patients given targeted therapies often develop tumors that appear resistant to a drug that was initially effective. CML patients develop resistance to imatinib/Gleevec via additional BCR-ABL gene mutations that directly result in reduced drug binding/potency. Additional drugs for CML have been developed to inhibit those novel BCR-ABL mutants that mediate acquired resistance.

Sadly, vemurafenib-treated patients also become highly resistant to therapy in a reasonably short time (see below). Interestingly, these cases do not develop mutations in BRAF, but instead, show new alterations throughout the MAPK pathway, as well as other unique cell growth circuits. Therefore, unlike CML, therapies designed to treat acquired resistance to vemurafenib will likely not aim to re-target BRAF. Instead, targeting alternate signaling components, such as ERK, may prove more beneficial.

 

Resistance mechanisms to BRAF targeting in melanoma part 1

 

Resistance mechanisms to BRAF targeting in melanoma part 2

Our ERK inhibitor (BVD-523) is a potent, selective small molecule that has demonstrated impressive in vitro and in vivo preclinical efficacy, and is expected to be effective in cancer settings where MAPK pathway addiction has been demonstrated. ERK inhibition may provide durable efficacy that is less complicated by acquired drug resistance, which would make BVD-523 a preferred agent for targeting MAPK signaling, compared to other similar drugs that target the pathway. Beyond its use as a single-agent, front-line therapy, we plan to assess whether BVD-523 may be effective in novel combination therapy regimens, as well as in specific genetic backgrounds that accompany acquired resistance. In total, targeting ERK with BVD-523, either alone or in combination with other drugs, may be a valuable strategy to treat safely cancers that exhibit aberrant MAPK pathway activity.

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