Targeting The Strong, Silent Type Of Tumor Is Challenging But Not Impossible
From a therapeutic point of view, having a bigger genomic mess is in some ways easier to deal with than a smaller one.
"In the case of the large majority of tumors with quiet genomes, current methods are challenging," Charles Roberts, director of the St. Jude Comprehensive Cancer Center, told the audience at a session on "Targeted Approaches for Cancers with Quiet Genomes" at the annual meeting of the American Association for Cancer Research in New Orleans in April.
The relatively low mutational load of such tumors presents different challenges for targeted therapies and immunotherapy.
Targeted therapies are directed against genomic alterations, which can work well in the case of an activating mutation.
But cancers with quiet genomes are often driven by the loss of a tumor suppressor. Roberts said that one recent publication estimated that tumor suppressor loss is nine times more common than oncogene gain as a cancer driver.
Roberts summed up the challenge in targeting those lost tumor suppressors as, "How do you target something that's not there?"
And an activating mutation in an oncogene does not mean you're home free. Oftentimes, oncogenes are transcription factors, which are considered undruggable by many.
Cancer immunotherapy, too, is less likely to be effective in cancers with quiet genomes, as its success is correlated with mutational load. Passenger mutations do not drive tumor growth, but they provide epitopes for the immune system to recognize.
Roberts cited a plenary talk by Ton Schumacher, professor at the Netherlands Cancer Institute, showing that some cancers have a mutational load that looks less foreign to the immune system than does a herpes virus infection. And like the herpes virus hides from the immune system without much trouble, such tumors will often manage to stay invisible as well.
Three speakers at the session described possible approaches to targeting such quiet tumors, both their own and those by others in the field.
John Bushweller, professor of molecular physiology and biological physics and chemistry at the University of Virginia, refuses to bend to the notion that transcription factors are undruggable – he has managed to drug one of them, a fusion protein of core binding factor beta and the smooth-muscle myosin heavy chain (CBF-beta/SMMHC).
Bushweller acknowledged in his talk that transcription factors are viewed as undruggable "for a number of good reasons."
Targeting transcription factors requires inhibiting protein-protein interactions, which often take place over relatively large, relatively flat surfaces. The interactions between proteins and DNA take place on surfaces that are convex and highly charged. Both scenarios are even harder to deal with than a deep binding pocket on an enzyme, which is challenging enough in its own right. Bushweller said the value of drugging transcription factors is that they allow the targeting of differentiation – an aspect of cancer that is not well served by current approaches.
Proliferation is well-targeted by kinase inhibitors, but blocks in differentiation – which keep cells in a progenitor or stem-like state that leads to proliferation in the first place – have received much less attention, even though Bushweller said good animal models exist for the problem.
"Cancers require hits both on proliferation and differentiation," he said. "Targeting the differentiation arm of the cancer problem has a lot of potential."
In work published in Science last year, and which Bushweller said he hopes to move toward the clinic and eventual commercialization with a biopharma partner, his team described developing an inhibitor for a fusion protein of CBF-beta and SMMHC. That fusion protein is present in about 10 percent of adult acute myeloid leukemia patients, the most common acute leukemia and one where no new treatment for relapsed disease has been approved in 40 years.
How to Target What's Not There
Session chair Roberts discussed ways of targeting an absence – cancers resulting from the loss of a tumor suppressor, specifically, the SWI/SNF chromatin remodeling complex.
Chromatin both organizes DNA and helps orchestrates its expression, making it more or less accessible to the machinery that transcribes it into RNA. For that reason, a single mutation can have large effects on gene expression.
Such is the case with SWI/SNF, a protein complex with 14 subunits. At least nine of those subunits are recurrently mutated in different cancers. Roberts and his group have done extensive work on one of those subunits, Snf5. The loss of Snf5 leads to the development of very specific tumors – T-cell lymphomas, and rhabdoid tumors, an aggressive pediatric cancer.
Rhabdoid tumors are literally as quiet as can be. In a 2014 comparative study, researchers from the Broad Institute found that rhabdoid tumors had the lowest somatic mutational rate of any cancer the group looked at, with an average of just four mutational events across the somatic genome.
In their work, Roberts and his team have uncovered what he termed an "epigenetic antagonism" between the SWI/SNF subunit Snf5 and another chromatin-targeting enzyme, Ezh2, during cancer development.
Mutations of Snf5 provide "an imbalance in the relationship" between the two enzymes, and that Ezh2 – which is also part of a complex, the polycomb complex – is essential for in vivo tumor formation after Snf5 loss. In further work, Roberts and his team have shown that many, though not all SWI/SNF mutated cell lines are sensitive to Ezh2 inhibitors.
Several such Ezh2 inhibitors have progressed into clinical trials. Furthest along is Epizyme Inc.'s EPZ-6438, which is in phase II for diffuse large B-cell lymphoma and follicular lymphoma, and in phase I for B-cell lymphomas and advanced solid tumors.
Additional Ezh2 inhibitors in phase I studies are CPI-1205 (Constellation Pharmaceuticals Inc.) for B-cell lymphomas, and GSK2816126 (Glaxosmithkline plc.), which is being tested in several lymphomas, solid tumors and multiple myeloma.
Rounding out the session was Stefan Pfister, a pediatric neuro-oncologist at the German Cancer Research Center. Pfister spoke about enhancers and their interplay with genomic rearrangements. Enhancers are genomic control regions that are distant from the gene they regulate. They cooperate with promoters to recruit transcription machinery.
Genomic rearrangements can "hijack" such enhancers, Pfister said, putting them in places where they can drive the expression of oncogenes. That phenomenon is well documented for Burkitt's lymphoma, where the oncogene myc is translocated so that it is driven by an enhancer for immunoglobulin genes.
Pfister's team has implicated enhancer hijacking in medulloblastomas, a group of aggressive pediatric brain tumors that have few recurrent driver mutations associated with them. Pfister and his colleagues have shown that two related proto-oncogenes, GFI1 and GFI1B, were activated via enhancer hijacking in a subset of medulloblastomas.
Importantly, there were different enhancers that could drive the expression of the two oncogenes in different tumors, meaning that genomes that looked different in terms of their rearrangements could lead to overexpression of the same genes.
More recently, Pfister's group has shown that atypical teratoid/rhabdoid tumors, another type of pediatric brain tumor, can also be classified into subtypes that are driven by different enhancers, and that this classification suggested different therapeutic targets according to subtypes.
Pfister said that beyond the implications for the specific tumor types they have looked at, his team's findings show how much remains to be understood about identifying genomic drivers of cancer. "The discovery phase in cancer genomics," he said, "is still ongoing."
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