MUSC background

Drug Discovery at MUSC, Part II

Bringing Promising Preclinical Findings to Clinical Fruition

“For cancer centers, it’s the holy grail,” notes Melanie Thomas, M.D., Associate Director of Clinical Investigations at MUSC’s Hollings Cancer Center, speaking of a cancer center developing a new drug from a concept, through extensive research and testing, to an actual first-in-human clinical trial. Hollings Cancer Center, the only National Cancer Institute–designated cancer center in South Carolina and one of only 66 in the country, has recently done just that with the Apogee trial, a first-in-human, first-in-class phase 1 clinical trial of a sphingosine kinase inhibitor. As Dr. Thomas notes, “Not all 66 cancer centers do first-in-human trials; lots of times researchers go with a contract research organization and the trials go offshore to Russia or elsewhere. For someone to stay here and trust us, it’s a vote of confidence.”

The Apogee Trial: First-in-Human, First-in-Class

The Apogee trial (“ABC294640 in Treating Patients With Advanced  Solid Tumors” [AB C -101; NCT01488513]) is a phase 1 trial of a sphingosine kinase inhibitor in patients with solid tumors who have not received benefit from standard-of-care chemotherapy. This trial is the first of a new category of drugs that act on a novel, lipid-based signaling pathway—the sphingomyelin degradative pathway. The research of Charles D. Smith, PhD, Professor of Pharmaceutical and Biomedical Sciences and Director of the Drug Discovery Shared Resource at MUSC, and others has shown the importance of this pathway in regulating cancer cell death and survival and thereby in supporting the development of resistance to chemotherapy and radiation by cancer cells. Dr. Smith hypothesizes that cancer cells could be made more sensitive and less resistant to chemotherapy and radiation treatment through inhibition of sphingosine kinase, a key player in this pathway and one that tilts it toward cancer cell survival and away from apoptosis (ie, programmed cell death). If proven efficacious and safe in clinical trials, sphingosine kinase inhibitors could substantially increase the clinician’s anticancer armamentarium, particularly when it comes to inflammation-associated cancers like pancreatic and hepatic cancer (for more information on the sphingosine kinase pathway, see “The Spingosine Kinase Pathway,” page 17).

A True Team Sport

The Apogee trial would not have been possible had not basic scientists and clinicians stretched beyond their comfort zones to communicate and collaborate together. Taking advantage of retreats sponsored by Hollings Cancer Center and the South Carolina Clinical  and Translation Research Institute (SCTR), Dr. Smith informed clinicians of the promising new compound, and the prospect of launching a trial of a compound for which MUSC investigators had done some of the basic science research kept everyone motivated. According to Dr. Thomas, “Everybody kept the foot on the gas pedal. As a group, people were really motivated to keep this going.”

Their motivation helped the study clear any number of hurdles that could have slowed momentum. For example, the investigational new drug application (IND) that must be submitted to the FDA to gain approval for a clinical trial can be a quagmire for many investigators. The IND for the Apogee trial, on which Dr. Smith (whose laboratory investigated the mechanism of action of the compound) and Dr. Thomas (who serves as the trial’s principal investigator) both collaborated, won speedy approval. Likewise, once the trial was approved, Stephen M. Lanier, PhD, Professor of Pharmacology and Associate Provost for Research, the clinical trials office and the institutional review board ensured that the proper boundaries were in place between Dr. Smith, the compound’s sponsor (he owns the startup company Apogee), and Dr. Thomas. Dr. Thomas is completely responsible for the conduct of the trial and the selection of patients; Dr. Smith has no direct involvement in the trial.

Why Aren’t There More Success Stories?

Sadly, such stories of the successful translation of promising new compounds from the laboratory into clinical trial through close collaboration between basic scientists and clinicians are too rare nationwide. Studies confirm that, despite substantial investment in biomedical research by both the government and especially the pharmaceutical industry, the number of new cancer drugs making it to the clinic has been disappointing.1 Kathleen T. Brady, M.D.,  PhD, Director of SCTR and Associate Dean for Clinical Research in MUSC’s College of Medicine, echoes this concern: “Our advances in the health of the nation have not paralleled the big investment in research.”

Many investigators falter as they attempt to make the transition from preclinical study to clinical trial, the so-called “valley of death.” According to Dr. Thomas, “the landscape is littered with drugs that got as far as animals and didn’t get any further.” Even after IND approval, only 1 in 20 drugs for which an application is filed makes it to market.2

Why is the track record for new drug approvals so poor? Why does it take so long for the drugs that do gain approval to make it to market and become available to cancer patients who desperately need them?

What We Have Here Is a Failure to Communicate

Poor communication between basic scientists and clinicians, between investigators and regulatory agencies, and between academic clinicians and community physicians can prevent or delay the arrival of promising new therapies in the clinic. Too often, according to Dr. Thomas, “clinicians and scientists live in parallel universes,” siloed into their own specialties with little time to communicate across the translational divide. Without communication, clinicians will never learn of promising new compounds in the laboratory and basic scientists will not be familiar with the clinical context in which such compounds might one day be used. More dialogue early in the design process between investigators and regulators could improve study design and increase the chances that a drug will be approved. All of the effort, dedication and monies needed to bring a drug through the four phases of clinical trials (see “The Four Phases of Clinical Research,” page 18) and into commercialization mean little if these novel therapies do not reach the patients who need them. Despite strong evidence of efficacy and safety from clinical trials, new therapies are sometimes not adopted by community physicians. Complicated drug regimens and dosing schedules that may be handled easily at academic medical centers where clinical trials are run may not be feasible in busy private practices. With feedback from physicians in private practice or at local hospitals, treatment regimens could be adjusted to maximize their practicality.

The High Costs of Clinical Trials

Many investigators simply run out of money to pay for the exorbitantly expensive clinical trials, particularly the large, complex, multisite phase 3 trials. Drugs that can show a statistically significant survival benefit versus available therapies stand the best chance for approval. Reaching sufficient power for statistical significance requires the recruitment of a large number of study participants, difficult at a time when only 2% to 3% of patients enroll in clinical trials.2 Establishing statistically significant survival benefit often entails waiting for enough patients in the control group to die, considerably prolonging the trial and delaying the drug’s entry into the clinic.2 This time-consuming and resource-draining process will inflate the price of any drug that is eventually approved, putting it outside the reach of many patients, particularly when reimbursement by Centers for Medicare & Medicaid Services and private insurers remains in doubt.2

An Antiquated Drug Approval Process?

Of course, ensuring safety and efficacy trumps concerns of cost effectiveness. However, some have questioned whether the current parameters for efficacy and safety set by regulatory agencies have become obsolete as our understanding of and approaches to treating cancer have changed.3 We once knew little about the underlying mechanisms of cancer and most anticancer agents were highly cytotoxic agents that were lethal to cancerous and healthy cell alike. However, much has changed in our understanding of cancer and how to treat it, as Dr. Harold Varmus, Director of the National Cancer Center, made clear in a visit to MUSC in June of 2012: “We have gone from a time when cancer was a complete mystery to a time now, just 20 or 30 years later, when we understand exactly the kinds of changes that occur in our chromosomes that turn a normal cell into a cancer cell and that has had profound implications for prevention, diagnosis and treatment.”

We know, for example, that cancer is not a single monolithic entity but a plurality of diseases. It is now classified not only by the organ it affects (eg, breast cancer) but by the genetic marker(s) with which it is associated (Her2+). Targeted therapy, in which an anticancer agent targeting a specific mutation is given to patients specifically with that mutation, is slowly replacing the blunt instrument of broadly cytotoxic agents. More broadly defined, targeted therapies can include those that knock out signaling pathways known to be linked to tumor growth and metastasis. Because of their precise aim, these agents are thought to cause less collateral damage to healthy cells and so, in the opinion of some, do not require the extensive and expensive studies in large animals currently required to identify a safe starting dose for phase 1 clinical trials. Likewise, the large phase 3 trials needed to establish survival benefit do not lend themselves easily to these targeted therapies and their more defined patient populations (patients with a cancer bearing a specific mutation). However, when tested in the target population, these drugs can have very high response rates.

Despite their promise, these drugs are slow to come to market as they attempt to meet antiquated criteria. Using a clinical end point other than overall survival could help break this log jam. Tumor response and disease-free progression have been suggested as possible surrogates of efficacy; clinical trials with such end points could be of substantially shorter duration. These suggested clinical end points have their drawbacks. Cancer is notorious for developing drug resistance; if one signaling pathway is blocked, it simply uses a redundant prosurvival or prometastatic pathway. A shorter-term clinical trial looking only at tumor responsiveness might miss the resurgence of cancer after the trial is over. Many proponents of the new end points think that increased vigilance during postmarketing surveillance could help address this potential shortcoming.

“Breakthrough” Legislation

Spurred in part by the outcry over recent severe drug shortages (see April/May issue of Progressnotes and page 3 of this issue for more on the recent drug shortages and how this legislation addresses them) and by continuing criticism of the cumbersome drug approval process, the U.S. Congress, in a rare show of bipartisan cooperation, passed the Food and Drug Administration Safety and Innovation  Act (S. 3187), on June 26, 2012. President Obama signed it into law on July 9, 2012. This legislation proposes streamlining the drug development pathway for “breakthrough drugs,” defined as those that are intended to treat serious or life-threatening disease and that have strong preliminary evidence of efficacy, as demonstrated by a clinically relevant end point.4

The definition of “a breakthrough drug” is key in this legislation. To be so designated, a drug does not have to demonstrate improved overall survival versus currently available therapy, the gold standard for approval until now. It must only show efficacy in improving one or more end points, such as tumor responsiveness or progression- free survival.

In addition to relaxing its definition of efficacy for these drugs, many of which are targeted therapies, the legislation also mandates frequent communication between regulators and investigators to ensure proper study design and efficient conduct of the trial.

This legislation represents the first reform of the FDA’s drug approval process for innovative therapies in more than 15 years (since 1997, when Fast Track was instituted). It addresses many of the obstacles that have slowed the flow of new drugs to the clinic, meaning that innovative new therapies could reach patients far more quickly and at a lower cost. Although cancers that initially respond well to such breakthrough drugs could develop resistance to them, the increased number of clinically available drugs will provide the building blocks of new combination regimens that could help prevent recurrence by blocking multiple pathways.

The result of all these changes could be a more nimble approval process that will allow the promise of personalized medicine and targeted therapies for cancer patients to become clinical realities.


1 Dorsey ER, Thompson JP, Carrasco M, et al. Financing of U.S. biomedical research and new drug approvals across therapeutic areas. PLoS ONE.  2009;4(9): e7015. doi:10.1371/journal.pone.0007015.

2 Schein PS, Scheffler B. Barriers to efficient development of cancer therapeutics. Clin Cancer Res. 2006; Jun 1;12(11 Pt 1):3243-3248.

3 Wagstaff A. Beyond survival – what should new cancer drugs have to prove and how? Cancer World. July/August 2011; 22-29.

4 S.3187--112th Congress: Food and Drug Administration Safety and Innovation Act. (database of federal legislation). 2012. June 25, 2012 Available at

This article originally appeared in the July/August 2012 issue of Progressnotes.


  • MUSC’s Hollings Cancer Center has succeeded in bringing an anticancer compound (a sphingosine kinase inhibitor) on which several laboratories at MUSC conducted mechanism of action studies to a first-in-class, first-in-human clinical trial (the Apogee trial), a rare feat even among National Cancer Institute–designated cancer centers.
  • Hollings Cancer Center is fully engaged in all phases of clinical research, with 219 clinical trials (127 of which are therapeutic) currently open and an additional 55 in the activation process; many of these trials are of innovative targeted therapies.
  • Nationwide, the number of new cancer drugs reaching the market is disappointing given the level of funding by industry and government, leading some to criticize the current drug development process as antiquated (based on an outdated understanding of and therapeutic approach to cancer) and overly cumbersome.
  • Barriers preventing more rapid availability of innovative new drug therapies to cancer patients include the high cost of all clinical trials, particularly the very large phase 3 trials needed to provide evidence of efficacy (ie, survival benefit versus standard therapy) to the US Food and Drug Administration; low participation rates by patients in clinical trials; and inadequate communication among basic scientists, academic clinicians and community physicians at critical junctures in the pathway.
  • Legislation recently passed by the U.S. Congress and signed into law by President Obama will streamline the approval process for “breakthrough drugs,” defined as those that are intended to treat serious or life-threatening disease and that have strong preliminary evidence of efficacy, as demonstrated by a clinically relevant end point.