By Allison Proffitt

June 29, 2018 | At MD Anderson, the Therapeutics Discovery team aims to develop new treatment options for MD Anderson patients in a much faster way. Two studies published in Nature Medicine earlier this month support the approach, they say.

Phil Jones, Vice President for Therapeutics Discovery has been at the MD Anderson Institute of Applied Cancer Science for about six years, and early on he noticed opportunities to connect stakeholders in what he believes is a unique way. “We really recognized the opportunities to connect the powerhouse of our clinical organization with a lot of the basic and translational stories that are coming out from our researchers,” he told Clinical Informatics News. It was a reasonable fit, he says, to add development efforts for novel therapeutics.

MD Anderson’s leadership—then-President Ronald DePinho, and now Peter Pisters—set up the Therapeutic Discovery team, which includes researchers from MD Anderson Cancer Center’s Institute for Applied Cancer Science and the Center for Co-Clinical trials.

“We assembled the Therapeutic Discovery division… to leverage that information, to pull together a team of people that really understands what is required to actually move a medicine—whether it be a small-molecule therapeutic, or a biologic or cellular therapy—through into the clinic,” Jones says.

The 100-person team comprises clinicians, researchers, and drug development experts, Jones says, working collaboratively to create new treatment options for MD Anderson patients. The team focuses on identifying candidates with, “all the right properties to be able to safely and effectively modulate a particular protein target pathway and evoke a response,” he explains, particularly driven by current institutional need, not a larger market.

“MD Anderson is a clinical operation and we're here to cater to those individuals; we're not driven by the commercial return here... We don't want to do exactly what large pharma and biotech are doing. We're looking to add onto that existing ecosystem,” Jones explains. For example, “We're not coming along with the next PI3K inhibitor or we're not coming along with the next PD1. We're trying to add to the armamentarium of different therapeutics available for our patients.”

But, of course, drug development costs money. The institution invested funds in the Therapeutics Discovery group to get started, and since then the group has pursued grants and partnerships—Jones mentions a partnership with GlaxoSmithKline. “The expectation is that at some point and time we can become cost neutral;” he says the team is “well on the way” to that goal.

The first published proof of the model came earlier this month with two Nature Medicine papers, both reporting findings from IACS-10759, a potent and selective inhibitor of oxidative phosphorylation (OXPHOS).

IACS-10759 is the first small molecule drug to be developed from concept to clinical trial by the Therapeutics Discovery team, Jones says, and the two published papers report its pre-clinical development. The first paper (https://doi.org/10.1038/s41591-018-0052-4) reports work led by Joseph Marszalek and Emilia Di Francesco that resulted in the discovery of IACS-10759 and its advancement into Phase I clinical trials for acute myeloid leukemia (AML) and solid tumors. A second paper, by Andrew Futreal and Yonathan Lissanu Deribe (https://doi.org/10.1038/s41591-018-0019-5), describes the potential of IACS-10759 for treatment of lung cancers harboring a specific epigenetic alteration.

Oxidative phosphorylation is known to be a key metabolic pathway in cancer cells, but it has been less targeted than glycolysis, “partly due to an incomplete understanding of tumor contexts where OXPHOS is essential,” Marszalek and his colleagues write. Through a “comprehensive translational effort across MD Anderson, we have identified multiple cancers that are highly dependent on OXPHOS,” Marszalek said in a statement, which drove development of the drug.

There are two ongoing clinical trials testing IACS-10759 at MD Anderson, Jones says. A phase 1 study led by Marina Konopleva and Naval Daver was launched in October 2016 and is evaluating IACS-10759 in acute myeloid leukemia. A second phase 1 trial was started last fall by Timothy Yap for solid tumor indications.

“Those two trials are going forward and moving ahead,” Jones says. “We're still in the process of dose escalating, so we still haven't picked what the actual dose will be, but we're approaching it. As soon as we've got that dose locked down, we're really looking to put biomarker-positive patients on the study here.”

The process of bringing IACS-10759 to this point has taken about 18 months, Jones says, and he expects that timeline to be reproducible. “It's where we wish to be; it's in the pack. We've subsequently done several other programs as well with a similar timeline here,” he says, referring to candidates that haven’t been announced yet.

The bulk of the drug development timeline still lies ahead for IACS-10759. But Jones is confident that the Therapeutics Discovery team’s early model is saving valuable time when it comes to delivering drugs to patients, and that it will continue to do so.

“This institution is really unique in its ability to do [research and preclinical development] at scale, and then to carry these programs all the way through itself into trials,” Jones believes. One of the key enablers of this success is the willingness to move quickly.

“We are very critical of the programs that we drive forward, so we try to do what we call ‘killer experiments’ up front to really understand which are the meritorious programs,” he says.  “We hold our teams accountable to do the experiment that's going to give us a reason to believe that this program is worth pushing forward toward the clinic. And if it's not for any particular reason, kill it fast.

“There is efficient decision making; we hold ourselves to a high bar. The programs that we think are going to be meritorious we resource accordingly and move those with an aggressive timeline. The ones that we think will not benefit our patients, we will terminate or we will park until more data becomes available.”