Symposium explores how new technologies are taking us from the bedside to the bench—and possibly getting us closer to the cancer moonshot.

Earlier this year, and not long after US Vice President Joe Biden paid tribute to his late son, Beau, by announcing a “moonshot” to cure cancer, an international collaboration to profile 10,000 tumors came to a close.

The Cancer Genome Atlas, a 10-year, US$100 million project had uncovered 10 million cancer-related mutations, an enormous achievement with nearly every aspect of cancer research benefiting from the effort, Johns Hopkins cancer geneticist Bert Vogelstein told Nature. TGCA had included 11,000 patients across 33 tumor types, representing the largest tumor collection ever to be analyzed for key genomic and molecular characteristics.

One of the cancer genes to emerge as a strong driver in tumor development is EZH2, which codes for EZH2, one of several enzymes that regulate chromatin, the molecules that package genes into chromosomes. Typically, EZH2 induces epigenetic changes—chemical modifications in DNA that alter the way genetic information is used by cells—in the histone molecules that wrap around DNA. EZH2, an acronym for ‘enhancer of zeste homolog 2’ in case you were wondering, figures in DNA methylation—when cells switch off genes they do not need by attaching methyl groups to certain sites along the DNA—and the transcriptional repression that is needed for the precise control of gene expression.

But studies have also found that EZH2 is highly mutated in some forms of cancer and highly expressed in numerous others, making it a reasonable target for targeted therapies. One company that has devoted a lot of time and money to EZH2 is Epizyme, a biopharmaceutical company headquartered in Cambridge, MA., that specializes in creating novel epigenetic therapies for patients with cancer. Their experimental small-molecule drug, Tazemetosat, which targets EZH2 mutations, was the focus of a talk during Tuesday’s symposium on novel technologies and platforms in oncology drug development. The symposium, held at Charles River’s reopened facility in Shrewsbury, was heavily focused on precision medicine, immune-oncology and epigenetics—three avenues that could really make a difference in cancer treatment for current and future generations.

Epigenetics, a hot research area across the disease spectrum, looks at how genes turn on and off in response to the environment. When identical twins are born they have identical DNA, but as they age their genes may be less similar due to all kinds of environmental factors that push genes to switch on and off. Cancer epigenetics specifically wants to know what changes in gene function turns a normal cell into a, well, terror cell.

Michael Thomenius, a principal scientist at Epizyme, said his company originally developed Tazemetosat for the two most common types of non-Hodgkin lymphoma (NHL), a type of blood cancer that strikes antibody-producing B cells and is often difficult to treat. In many types of tumors, EZH2 is overexpressed, but in these types of NHL, the EZH2 harbors mutations that impair the enzyme’s ability to methylate the histone. Oddly, the NHL patients studied by Epizyme always carried both a regular and a mutant copy of EZH2, leading investigators to ultimately conclude that both good and bad forms of EZH2 had somehow struck an unholy alliance to trigger lymphomas.

In a dose-escalation study, nine of the 16 NHL patients bearing the EZH2 mutation had an objective response, including a 53-year-old female whose tumor deceased dramatically by week 16 and had maintained the decrease by week 40. While NHL was the original focus of Tazemetosat, it is also being tested in patients with drug-resistant solid tumors (kidney and ovary) and other deficient chromatin regulators such as INI1 or SMARCA4. A Phase II study of two types of NHL is now open for enrollment in Australia, France and the UK. The company is also pursuing a study in children who have an aggressive form of tumor that forms primarily in the kidney.

Molecular Biopsy

Craig B. Thompson, the president of Memorial Sloan Kettering Cancer Center in New York, who also spoke at the symposium, said epigenetics is teaching us that cancer is not a disease of cell proliferation but is really about cells that have forgotten how to differentiate.

The more we learn about the genetics of the tumor and the patient, the greater the opportunities are to tailor treatments that have a better chance of working, and to add more novel therapeutics to the pipeline.

For instance, most clinical trials typically enroll patients with the same kind of cancer, such as lung, colo-rectal, breast, etc. But Thompson said MSKCC has begun to join together relapsed patients from across the cancer spectrum who share the same molecular lesions to see how well they respond to drugs that have been effective against those lesions.

Every patient at MSKCC gets molecular sequenced, which is helping to make their treatment more precise. Thompson predicts that within the next five years, this will be the norm nationwide, with every cancer patient facing treatment eligible for a reimbursable sequencing test.

Tuesday’s symposium also included several talks about immuno-oncology, the major driver of drug development today. The topics ranged from the use of cancer immunophenotyping as a way of predicting therapeutic response to the range of mouse models that can help drug developers identify novel pathways in immuno-oncology. There was also a nifty discussion about mouse hospitals, which allow scientists to test treatments on mice in the same way humans are treated.

How to cite:

McEnery, Regina. Rocket Science. Eureka blog. May 12, 2016. Available: http://eureka.criver.com/rocket-science/