Finding the Achilles’ heels of tumors
There are lots of ways of imagining how tumors are able to forge such a destructive path in the human body. How about the energy from a non-stop sugar high? The most destructive tumors are, almost inevitably, the ones containing the largest cells and they get that way, in part, by gobbling up huge amounts of glucose.
The players and pathway that contribute to this chain reaction in the life cycle of tumor cells has been a major focus of cancer biology over the past decade or so. Some of those discoveries and theories are now informing new avenues in cancer therapeutics—from novel antibody and T cell immunotherapies to epigenetic changes and personalized approaches for early classes of chemotherapy drugs. President and CEO of Memorial Sloan-Kettering Cancer Center Dr. Craig Thompson, whose lab has been at the forefront of breakthroughs in cancer biology and immunology, helped set the stage for this transition in thinking, and he has since developed translational therapies that exploit the metabolic addictions exhibited by cancer cells.
Yet when it was first suggested that 70% of human cancers were likely related to nutrient metabolism such as the tyrosine kinase receptor and other members of that pathway, the academic research community laughed out loud, recalled Thompson during his opening talk at the New Approaches to Cancer Drug Discovery symposium at Harvard Medical School on Oct. 14. Charles River sponsored the event, the third in a global series on cancer innovations.
Cells don’t just scoop up sugar “willy nilly” says Thompson, but what triggered the scavenger hunt that enabled resting cells without an effector function to double in size and begin to proliferate and mutate was unclear at first. Researchers theorized that signal transduction was activating receptor tyrosine kinases (such as insulin and growth factor receptors) outside cells, setting in motion a cascade of events inside cells that enabled the errant cells to build their lipid and protein contents. How to exploit and derail these events is a hot topic in cancer research now.
Preventing tumors from proliferating has been a long-time goal of cancer therapy, of course, but cancer biology and immunology is opening doors to new ways of attacking and thinking about the disease. Thompson’s lab, for instance, is focusing on trying to block lipid metabolism—the most critical step in fatty acid synthesis.
Nimbus Discovery (whose Chief Scientific Officer Rosana Kapeller spoke at the symposium) has developed novel inhibitors that block an enzyme in fatty acid synthesis up-regulated in many types of cancer.
Epizyme (also represented at Tuesday’s symposium) has discovered small molecule inhibitors of the gene EZH2 (for “enhancer of zeste 2 polycomb repressive complex 2 subunit’’ in case you wondered) that provides instructions for an enzyme that modifies histones, structural proteins that bind to DNA and give chromosomes their shape. The inhibitors, one of which has entered clinical trials, are designed to target subsets of human cancers bearing defined genetic lesions.
Another approach highlighted at the symposium involves making a nanoparticle that binds to albumin in the blood, which in turn allows internalization of the nanoparticle so that it can bind to DNA and kill the cancer cell. The nanoparticles contain a platinum drug such as cisplatin and measure around 100 nanometers, roughly 1/1000th the size of a single human hair! The goal for Blend Therapeutics, which is developing the platinum nanomedicines, is to use the albumin—which some cancers take up in large quantities—to try and drive more of the platinum drug into tumor tissue, says Richard Wooster, Blend Therapeutic’s Chief Scientific Officer.
There were a number of other interesting projects highlighted on Tuesday, and Eureka plans to explore some of them individually in future blogs.
Thompson says cancer researchers no long consider cell proliferation the most interesting part of cancer. Epigenetics—in this instance functionally relevant changes to the genome that do not involve a change in nucleotide sequences—has contributed to this paradigm shift by showing that epigenetic states are as important in tumor formation as gene mutations.
The hope is that these altered states prove more vulnerable to therapies than the cancer itself.