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Taking a Translational Approach to 'Incurable' Cancers

Taking a Translational Approach to 'Incurable' Cancers

Cold Spring Harbor Laboratory

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It's called "the valley of death," that gap between an elegant breakthrough in basic science and the arrival of a new therapy based on that breakthrough, and it is where brilliant ideas go to die. But not if the Cancer Therapeutics Initiative (CTI) at Cold Spring Harbor Laboratory (CSHL) has anything to say about it. For years, policy makers, patients, and even many scientists have lamented the disconnect between basic biomedical research, which the United States does superlatively, and the lower-profile work that turns discoveries into therapies. The barriers to such "translational" research aimed at moving discoveries from bench to bedside are legion, and they are why headline-making discoveries seldom become treatments, much less cures.

The goal of the Cancer Therapeutics Initiative is to discover new, non-toxic therapies for currently incurable cancers by designing drugs that will target the genetic mutations that drive a tumor and the pathways by which that mutation exerts its malignant effects.

The CTI will do that through what it calls a "vertically integrated" approach—but the MBA-speak doesn't do justice to how revolutionary the approach is.

In the standard model, molecular biologists might discover, say, a gene required for the survival of leukemic cells. Then, because the discoverers usually don't have the expertise to design a molecule able to cripple that gene and test it in animal models of leukemia, it is up to many other teams to carry the discovery across the goal line to an FDA-approved drug. With the CTI, research teams will do it all, from rapidly identifying new therapeutic targets to performing the therapeutic development and initial validation required for human trials.

The process starts with the genetic analysis (profiling) of patients' normal and tumor DNA samples to identify a given tumor's Achilles heels. But while other labs might make that discovery and call it a day, CTI scientists will then identify and develop molecules with significant activity against these targets. Next, another team will churn out sophisticated mouse models of the particular cancer—that is, mice carrying the same genetic glitch identified in human tumors—on an industrial scale. Finally, researchers will validate in the mice both the targets and the molecules designed to "hit" them, gleaning clues to how cancer patients are likely to respond. The result should be a molecule ready to license to a biotechnology firm or pharmaceutical company for human testing.

This soup-to-nuts approach is a novel adventure in an academic setting. By taking it, CSHL is building a powerful translational engine that will convert academic knowledge about cancer into new targeted treatments. First up: prostate, pancreatic, breast, ovarian, liver, lung, and brain cancers, as well as melanoma and leukemias.

We seek to maximize the impact of what we in academia do best: discover functionally meaningful targets for new cancer therapies."

The CTI approach has already shown promise. CSHL's Christopher Vakoc and colleagues, for instance, used RNA-interference technology developed in the lab of CSHL's Greg Hannon to discover that a protein called BRD4 drives an acute, usually incurable form of leukemia called AML. Shutting down BRD4, the team confirmed, derailed a cellular process considered the hallmark of AML—the aberrant self-renewal of leukemic stem cells and their failure to mature. Scientists had previously found that a drug called JQ1 hits BRD4, so the CTI team then showed that JQ1 causes remissions of cancer in mice modeling human AML. Now, a variant of JQ1 is in clinical trials.

A single drug against a given form of cancer is unlikely to be sufficient, however. To turn lung cancer, for instance, into a chronically manageable illness rather than a frequently fatal one, therapies will have to anticipate and disable molecular pathways that evolving tumor cells develop to circumvent the firstline treatment, much as insects evolve resistance to pesticides. This will call for the development of combinations of targeted drugs, which will be taken in "cocktails" analogous to the multi-drug combinations used so effectively to overcome the resistance that develops in people infected by the HIV-AIDS virus.

The CTI was conceived and is led by CSHL's President & CEO, the distinguished cancer researcher Bruce Stillman. It also benefits from the insights of James D.

Watson, CSHL Chancellor Emeritus, co-discoverer of the double helix structure, and Nobel laureate; and the expertise of David Tuveson, a renowned clinicianscientist and director of the CTI.

"We seek to maximize the impact of what we in academia do best: discover functionally meaningful targets for new cancer therapies based on our deep knowledge of cancer biology," says Stillman. "The CTI aims to deliver well-validated drug candidates to industry. Industry can then focus on what it does best: optimizing candidate molecules and testing them in cancer patients."

CSHL envisions collaboration with other research and clinical centers as well as biotech and pharmaceutical companies that can both contribute to and benefit from the vertically integrated CTI pipeline. Collaborators include many New York-based institutions, including Memorial Sloan-Kettering Cancer Center, The Rockefeller University, Stony Brook University, Weill Cornell Medical College, Columbia University Medical Center, NYU Langone Medical Center, and North Shore-LIJ Health System.

New York and Cold Spring Harbor Laboratory, which began as a summer biology camp for city teachers in 1890, have been great partners in biomedical research and education for the last 120-plus years.

The lab has been a magnet for the best and brightest biologists and geneticists, attracting more than 12,000 professional scientists from around the world each year to an internationally renowned program of scientific meetings and technical courses.

Proximity to New York City and a harbor-side site on the beautiful North Shore of Long Island makes CSHL a desirable location for researchers and aids with faculty recruitment. In addition, Long Island has the resources and highly trained technical workforce that the CTI needs. Within the next decade, says Watson, research like that at CTI may well "break the back of 'incurable' cancers."

Photo: CSHL cancer researchers at work.