publication date: Feb. 5, 2016

 

Slamming the Door

Part II: Cancer’s Butt

 

This series re-examines the concurrent controversies at the Cancer Prevention and Research Institute of Texas and MD Anderson Cancer Center. This examination is possible in part because of new insight provided by Alfred Gilman, a Nobel laureate who served as the first scientific director of the state institution that distributes $300 million a year. Gilman died on Dec. 23, 2015.

Part I of the series appeared last week.

 

CPRIT’s review process appeared to have become a major annoyance to those who wanted to redraft the criteria for dispensing the princely sum of $300 million a year. Texas geography and Texas politics did matter—a lot.

The cross-state competition between MD Anderson Cancer Center and UT Southwestern Medical Center proved to be especially important.

MD Anderson has long been a clinical powerhouse, the kind of place you go with a complicated cancer. If it ramped up its basic science, the cancer center would be better positioned to understand the origins of cancer and make more fundamental contributions to treatment of cancers, including discovering useful drug candidates and moving them from the bench to the clinic.

The place is rich with doctors you would want to treat your mother, but none of its faculty members had won the Nobel Prize. The UT Southwestern faculty of the Dallas institution included five Nobel laureates. And year after year, MD Anderson would trail UT Southwestern in the number of CPRIT grants

In 2011, the oncopolitical map of Texas was to be redrawn.

MD Anderson was recruiting a new president, and the job of MD Anderson president doesn’t open often. Over the preceding 70 years, the institution has had three presidents: R. Lee Clark (1946-1978); Charles LeMaistre (1978-1996), and John Mendelsohn (1996-2011).

The regents were considering two leading candidates. Raymond DuBois, the MD Anderson provost, was an inside candidate who understood how a structure as complex as MD Anderson functioned. In 2007, DuBois surprised oncology insiders by leaving the job of director of the Vanderbilt Ingram Cancer Center to become the MD Anderson provost.

Observers pointed out that DuBois, whose name is pronounced in the Anglo rather than the French manner, is a native Texan. He was born in the farming and ranching town of Runge, around 75 miles southeast of San Antonio. Surely, DuBois, an expert in colon cancer, was given assurances that he would get a good shot at becoming the next president of MD Anderson, observers presumed.

Since his duties as provost were to promote the center’s academic mission, DuBois kept his hand on MD Anderson’s money spigots. His principal mission was to boost the center’s basic research programs. Others pointed out that DuBois is not a predator. He is uniformly described as a nice guy, who doesn’t begin his mornings by determining whose career he would gut by sunset. Could someone like that be entrusted to run MD Anderson?

The second candidate was Cheryl Willman, director of the University of New Mexico Cancer Center, whose work is focused on leukemia. Willman is a solid administrator who has run her cancer center since 1999.

Another candidate, Brian Druker, co-developer of the drug Gleevec, which made it possible to control chronic myelogenous leukemia, bowed out early. According to knowledgeable sources, Druker, director of the University of Oregon Knight Cancer Institute, a place much smaller than MD Anderson, had one meeting with the search committee.

Asked how he would approach the job, Druker told the committee that during the first years he would want to engage the faculty in developing a strategic plan. After all, MD Anderson is a complex, functioning structure that has to be handled with care.

Druker noted that MD Anderson is extraordinarily highly regarded for its clinical research and that he would want to make sure that it remained well-supported and even enhanced to do precision medicine trials.

In addition, the level of science supporting pre-clinical and clinical studies needed to be strengthened, and it would be incumbent upon the new president to look for opportunities to ensure this happened.

In the job interview, Druker emphasized his enormous respect for the institution and said that any changes he would make would be in an effort to further increase its reputation and impact.

Ultimately, Druker decided to stay in Oregon, building a billion-dollar program focused on the molecular characteristics of cancer in order to treat diseases before they become lethal (The Cancer Letter, Aug. 1, 2014).

Later, I would obtain a copy of an email in which Kenneth Shine, then the UT System executive vice chancellor for health affairs and head of the search committee, announced Druker’s decision not to pursue the job:

“I am sorry to report that after extensive discussions with his wife, Brian Druker has withdrawn from our search. The principal issue revolved around the need to be the public face of MDACC and the needs of his three children and family, which he felt would suffer from these obligations as well as other duties of the President. I discussed several options in this regard with him, but to no avail. I would propose to continue with three candidates.”

Many cancer centers are run by chief executives who are basic scientists. However, the UT System requires that the presidents of its health organizations have MD degrees. This would make sense at Anderson, a huge clinical enterprise. The help-wanted ad posted by the UT System read:

“MD Anderson’s next President will be a licensed physician possessing an M.D. degree with at least five years of experience practicing medicine; distinction in scholarship and practice; present a strong scientific background; a substantial commitment to patient care, education, and research; management experience appropriate to overseeing a $3.2 billion enterprise of 17,000 employees; and will convey well-established leadership, communications, and interpersonal skills along with a genuine passion for MD Anderson’s mission to treat and eliminate cancer.”

The regents quickly focused on a Harvard power couple: Ronald DePinho, a scientist focused on drug development, and his wife Lynda Chin, a genomic scientist. DePinho was vying for the job of president and Chin was being recruited to serve in a senior scientific position.

 

 

On May 11, 2011, a colleague, Todd Ackerman, called me from the Houston Chronicle.

“Have you ever heard of Ronald DePinho?” he asked. The name didn’t ring a bell.

I searched my memory. I searched my emails. I searched the documents on my computer. All I could see was that DePinho was a subscriber to The Cancer Letter.

“No. Definitely not. Of course, this doesn’t mean anything. I guess it can mean only that the regents chose to give the job to someone less well known, someone younger. It could be the right thing to do; probably is. After all, the guy is from Harvard.”

Then I pilfered a line from Woody Allen: “That said, Harvard makes mistakes. Henry Kissinger taught there.” I should stop using that line.

I made a call or two and learned that DePinho was, in fact, very well known in basic science circles.

I couldn’t see how I could possibly contribute to coverage of selection of the next president of MD Anderson. Unlike Todd, I didn’t understand the mechanics of the UT Board of Regents, didn’t have the sources I’d need to get the bearings straight. I hate being beaten, but at least I had an excuse: I didn’t have boots on the ground. And it helped that I like and respect Todd.

To see what I was missing, I looked back at Todd’s coverage, zeroing in on a juicy tidbit: DePinho had been a guest on Colbert Report. I found the segment.

It was hilarious. DePinho was a suit-wearing gray-haired guy, a perfect foil for Colbert, also a suit-wearing guy.

Colbert invited DePinho to discuss the finding that it was possible to reverse aging in genetically engineered mice. To explain this, Colbert brought out a massive, plush model of a chromosome. The thing was large and, in an exaggerated way, phallic. This set the tone for the conversation.

DePinho remained unflappable as Colbert massaged his preposterous “chromosome,” noting that the tip—the telomere—was its most sensitive part. DePinho seemed to be channeling his discomfort into comedy. Was this intentional on DePinho’s part? Was it accidental? Where is it written that humor has to be intentional to be genuine?

Whatever it was, it worked. At one point, DePinho started tearing off pieces from the red telomere to demonstrate what happens when we age. As the level of discourse spiraled downward, I started to think that DePinho will be a fun center director to cover.

I called some friends at Harvard, who told me that DePinho had an aggressive style and was certain to ruffle some feathers. I learned that DePinho and Chin worked so closely together that at Harvard they were nicknamed DeChinho.

Also, I learned that some folks in Cambridge put together a betting pool, stratifying predictions of how long DePinho would last at MD Anderson. Moving aggressively isn’t necessarily a bad thing, I thought. The guy had to be cool.

DePinho’s board certification is in internal medicine. In 1998, he moved to Harvard from the Albert Einstein College of Medicine in New York, yet he was still licensed to practice medicine in New York. He appeared to have seen no need to get a medical license in Massachusetts, and records showed that, similarly, he had no license to practice in Texas.

DePinho focused on applying genomic leads to selecting compounds for future drug development. One of the drugs he helped select for testing—tivozanib—was going through the final phase of clinical testing. Having a drug in phase III trials represents the penultimate bragging rights for a cancer doctor. The ultimate bragging rights, of course, would be having the drug approved and used for the benefit of patients.

The company that was co-developing tivozanib—AVEO Pharmaceuticals Inc.—had been started by DePinho and Chin.

On May 11, 2011, the day he was chosen to lead MD Anderson, AVEO was trading at about $17 a share, which meant that the 626,000 shares owned by the DePinho family were worth more than $10.6 million. FDA approval would be certain to push the stock value even higher.

DePinho and Chin were involved in other companies, too, though none were as close to payday.

Tivozanib was licensed from a Japanese company. AVEO’s and DePinho’s expertise was said to be in relying on technology for choosing drugs rationally, taking the guesswork out of drug approval. This technology could be applied equally to making new compounds and unlocking the potential of existing compounds.

As they considered DePinho’s candidacy, the regents had little reason to doubt that tivozanib would work. Ron was confident and, after all, the drug was chosen rationally, based on emerging science.

 

 

Later, I would obtain a copy of DePinho’s application letter. The letter, addressed to Kenneth Shine, the UT System executive vice chancellor for health affairs and head of the search committee, was informative, even illuminating.

“MD Anderson’s next leader must continue to nurture its strong programs in clinical care, while building world-leading multidisciplinary teams that are focused on the basic mechanisms of cancer and driving such science toward clinical endpoints,” DePinho wrote. “In this broad context, I wish to convey that I appreciate the challenges facing the institution with a budget of $3B where the majority of its operating budget derives from patient care, yet facing health care reform, reductions in state budgets, and contracting NCI pay-lines—the latter impacting not only finances, but also weighing heavily on the psychology of our next generation.”

There is a lot to unpack here.

MD Anderson’s engine—clinical revenues—has to grow, or at least remain the same. On top of that, new money has to be found to finance a massive expansion into basic science. While the opportunities around it withered, MD Anderson would have to grow. Some other funding opportunities were needed; philanthropy, CPRIT, and pharmaceutical companies would have to play a role in this growth.

The letter was also a reminder about the impossible feats directors of large cancer centers are expected to perform.

In addition to being a world-class scientist, the president of MD Anderson had to be the chief administrator of a $3 billion health system. The job required a scientific vision and an administrative prowess that somehow had to produce a coherent multi-year strategy.

The psychology component is fascinating, too. DePinho seems to be suggesting that during these difficult times, physicians and scientists need to be given a glimmer of hope.

 

 

DePinho and Chin had a flashier sales pitch than DuBois and Willman.

While DuBois and Willman were solid scientists and experienced administrators, DePinho and Chin were experts in “personalized” medicine, genomics, the science that seeks to bring the right drug to the right patient, even engineering unique cures intended for just one patient.

As interviews continued, the couple promised to make MD Anderson into a very well-funded institution by inviting in the pharmaceutical industry and making it easier to develop drugs.

An entire unit—an institute—would be created for the purpose of finding and rapidly testing compounds. Some of these compounds would come from MD Anderson researchers. Others would be brought in by the industry.

The institute would, in effect, represent a hybrid of academia and industry. The place would be operated by Chin. And how could you dispute that DePinho and Chin understood what makes the industry tick? They were founders of several companies and had a multi-million-dollar portfolio to show for it.

In a nutshell, this pair would link academia with industry, finding new cures, and bringing millions—perhaps even billions—in new funds to MD Anderson.

On May 11, 2011, the UT System Board of Regents met in closed session to interview the three candidates, DuBois, Willman and DePinho.

Candidates came in one by one, and one by one they left.

Then the decision was announced: the job would go to DePinho.

In a statement announcing the selection, Regents’ Chairman Gene Powell praised DePinho as “a distinguished scientist and proven administrator capable of leading the nation’s premiere comprehensive cancer center, UT MD Anderson.”

While it was technically okay to call DePinho an “administrator,” the program he ran—the Belfer Institute for Applied Cancer Science—was minute by comparison with MD Anderson.

According to DePinho’s application letter, over a decade, Belfer secured $100 million in grants, $50 million in donations, and another $50 million in corporate alliances. By way of comparison, MD Anderson is a massive enterprise that employs nearly 19,000 people, occupies 11.5 million square feet of space and has the revenues in excess of $3 billion.

Chin would also join the faculty of MD Anderson, the UT System announced that day. Chin received her medical degree from the Albert Einstein College of Medicine and her research interest is in cancer genomics and cancer biology. She worked with her husband at Dana-Farber, too, as the scientific director of the Belfer Institute for Applied Cancer Science. She was also a professor of dermatology at the Harvard Medical School and department of medical oncology at Dana-Farber Cancer Institute.

As a basic scientist placed in control of a massive clinical enterprise, would DePinho understand what MD Anderson clinicians do? Would he understand the complexity of clinical trials? How would his wife and collaborator fit into the delicate political fabric of the state institution? Would DePinho have the humility to acknowledge that there are things—vast areas, in fact—where he knows next to nothing? Would he have the wisdom to ask questions, to delegate? Would he choose the right people to guide him?

These were vitally important questions, because MD Anderson is a huge operation that has a very small profit margin. It looked like Ron and Lynda landed very lucrative positions, even for a couple whose AVEO stock was worth more than $10 million. DePinho’s compensation for the first year was $1.8 million, and Chin’s $813,000.

 

 

By the time Ron DePinho and Lynda Chin appeared on the scene, CPRIT spent over $670.7 million on research within the state and on helping recruit scientists from the outside.

Altogether, $489.6 million went to academic research, $111.4 million went to commercialization, and $69.7 million went to prevention. (Research on prevention came from the research budget.)

DePinho and Chin could impress the UT System Board of Regents, the MD Anderson Board of Visitors, but Gilman’s crew would give them their due; no more, no less.

In October 2011, DePinho addressed the Board of Visitors:

“In this decade, the cancer genome atlas will provide scientists with the list of genes that are mutated in cancer.

“With the complete list of mutated genes in hand, we will make use of our newfound ability in functional genomics to silence specific genes at will. We can see if the extinction of a mutated gene causes the cancer cell to die. We anticipate that there will be several hundred genes playing critical roles in cancer and our goal will be to identify every one of these rogue genes. It is important to appreciate that going after a single target will not lead to cure. Cancer DNA is highly unstable, allowing for emergence of resistance. Thus, the key to success will be to determine which combination of targets will need to be co-extinguished in order to elicit durable responses, i.e., cure. This is key—there is no single magic bullet.

“With that list of key drivers, we can genetically engineer perfect models of human cancer. Test drug and drug combinations. Needed are combination strategies – designed to co-extinguish multiple cooperative targets as well as harness the power of the immune system to eliminate every last cancer cell in the body.

“Once drugs are in hand, we need sophisticated mouse model systems to enable testing of combinations prior to clinical testing, and we need a clinical trial design that incorporates the genotyping to select tumors with those targets. This is the future of treatment at MD Anderson.

“Cancer is not simply about treating advanced cancers. It is also critical that we develop robust preventive strategies that will quell the largely unknown processes responsible for causing cancer in the first place. If we can understand these processes, then we can monitor them and control them. Here, there are exciting advances in our understanding of the underlying circuitry of aging—given that age is the most important risk factor for cancer, such molecular insights are providing new therapeutic points of attack to reverse the aging process and diminish the incidence of age-related diseases. These are historic times indeed.

“Early detection is another important area, providing an enormous opportunity to impact on the cancer problem in the near term. There is a revolution in serum proteomics and imaging that will enable us to diagnose cancers at much earlier stages where the chance for cure is greatest. This is good news. However, these advances will fuel new challenges in the accurate management of these early stage cancers. Witness the impact of PSA testing in prostate cancer. Today, this nation spends from $500 million to $1 billion in unnecessary interventions because we do not have the molecular markers needed to identify which 15 percent of the 220,000 cases will go on to die of the disease. It is estimated that for every life saved, we treat close to 50 men.

“To accomplish our moon shot, full knowledge and powerful technology will not be enough. We need new organizational constructs as well.

“The current drug discovery and development ecosystem is not optimally configured to systematically drive discoveries to clinical endpoints that make a difference in patient’s lives. Historically, discovery in academia has created new biotech companies that, in turn, fuel the pipeline for large pharma who have the capital and commercial abilities to move assets into mainstream use.

“This ecosystem has a 95 percent failure rate in cancer drug development with 56 percent of failure occurring in late stage testing. Huge cost. It is my view that a major cause of these failures rests on the inability of the biotech industry to conduct the deep analyses needed to validate targets and drugs at the preclinical stage.

“And the situation has gotten worse with the near-collapse of the biotech industry which will translate into fewer assets for pharma to buy in the years ahead.

“Academia has been and will continue to be a caldron for innovation but I believe that it must also be further optimized organizationally to drive discoveries into effective drugs in the clinic.

“A new organizational construct is needed that will systematically validate targets, develop drugs against those targets, test them in sophisticated models and bring them forward to the private sector.”

Gilman, who was deeply involved in drug discovery and commercialization (he was also on the board of Eli Lilly & Co.), didn’t share DePinho’s outrage about the high failure rate of drugs in late-stage trials of cancer drugs. “Depending on his definitions, this is no different from all other areas of drug discovery,” Gilman said to me. “And of course many of those failures are because of uncommon adverse events that can only be discovered in later stages of human trials.

“In my view, a lot of the problem is biotech companies running poorly controlled phase II studies so they get the results they need to get more funding and get the stock price up. Many are not interested in actually getting a drug. They are more interested in a profitable strategy for early exit.”

At the time, DePinho’s ideas about the “new organizational construct” seemed intriguing. Was he really suggesting building something reminiscent of a pharmaceutical company within MD Anderson?

 

 

The words “the cure” seemed to have flashed in DePinho’s early remarks. According to the Chronicle, On May 11, in his post-selection comments, on May 11, 2011, DePinho said:

“We’re now positioned to make an assault on a disease that’s truly dreaded worldwide. I give you my word that I will give it my all to keep (M.D. Anderson) the world-class (institution) it is and bring the best science to make it reach its ultimate potential—nothing less than curing the disease.”

In November, 2011 two months after he moved to Houston from Dana-Farber Cancer Institute, at a fundraising event in San Antonio, the researcher, who is also a martial arts expert, pledged on camera to “kick cancer’s butt.” (The Cancer Letter, Oct. 12, 2012.)

I bounced this statement off Gilman.

“Are you sure he said ‘cancer’s butt’ and not ‘cancer’s butts’?” Gilman asked. “Had he said butts, I would have found it less problematic.”

Cancer, after all, is an uncounted multitude of diseases, and if you insist on taking the anthropomorphic route, you would be required to give each of them a separate butt, Gilman explained.

They don’t give out Nobel Prizes for nothing.

Copyright (c) 2020 The Cancer Letter Inc.