The Magazine of The University of Massachusets Medical School Vitae:

'World-Class' Discovery, UMass Cancer Center Director Dario Altieri, M.D. receives a unique federal award to seamlessly guide a disease-killing compound from lab to clinic, by Lynn C. Borella

Often uttered in hushed tones or associated with the phrase "going to battle," it's a word that evokes fear in the hearts of most people.  It identifies a disease characterized by an uncontrollable spread of abnormal cells in any organ or tissue of the body and one that comes in varied forms and affects any age, race or gender.  No one is immune, and if surveyed, most people could name at least one individual they've known who has either survived or succumbed to the disease.

No doubt the word that springs to mind is "cancer."  Wouldn't it be revolutionary if an anti-cancer agent could target and destroy cancerous cells just as precisely as our minds can conjure this distinctive disease?  But  how far away is such a cure?  Investigators at the University of Massachusetts Medical School are hoping to answer "sooner than you think."

A novel molecule called "shepherdin," which selectively kills tumor cells while sparing normal cells nearby, was recently discovered in the laboratory of UMMS Professor and Chair of Cancer Biology Dario Altieri, MD, the Eleanor Eustis Farrington Chair in Cancer Research and the medical director of the UMass Cancer Center.  For this breakthrough, which has proven to have an impact on a wide variety of cancer, regardless of their origin or genetic makeup, Dr. Altieri has received an exclusive award from the National Cancer Institute that will aid in moving this potential anti-cancer agent from bench to bedside for the benefit of cancer patients worldwide.

The evolution of shepherdin starts with a protein that Altieri, a nationally renowned hematologist, discovered in 1997.  Called "survivin," this molecule was not only found to be overabundant in tumor cells, but also helped to protect them from apoptosis, or programmed cell death, thereby allowing for unchecked tumor growth, a hallmark of cancer.  Given these protagonist attributes, survivin has since become a target of choice for cancer researchers worldwide, including Anthony W. Tolcher, MD, director of clinical research at San Antonio's Institute of Drug Development, Cancer Therapy Research Center.  "Dr. Altieri's discovery of survivin has played a world-class role in oncology," he said.  "There have been many discoveries in cancer research, but few have lead to target identification, and few still to clinical studies of inhibitors."

Based on his work with survivin, coupled with studies of a second protein called Hsp90 (Heat Shock Protein-90) that "chaperones" survivin to ensure its delivery into cells, Altieri sought an antagonist that would interfere with the function of both proteins.  The result was shepherdin, which binds to Hsp90 and blocks its ability to work with survivin.

"How we came across shepherdin was through a molecular screening we had done to identify new compounds that could block survivin," Altieri explained.  "What we observed was that shepherdin had three properties that were very important when thinking about development of a therapeutic; it was very effective in killing tumor cells; it was selective in killing only the cancerous cells, and it was effective in vivo [in the body], reducing tumor formation in both human tissue cancer cell cultures and animal models, while providing non-toxic to organs and normal tissue."

Following publication of these findings in the May 2005 edition of Cancer Cell, a high-impact scientific journal, Altieri's next question was, "Where do we go from here?" "Our laboratory is committed to continuing its investigations into the properties of shepherdin as an antagonist to survivin, but we also are interested in pushing promising compounds into the clinic," he said.  Altieri looked to the UMMS Office of Technology Management to identify potential commercial collaborators.

One possibility - and the answer for Altieri - came in the form of a valuable resource that is open only to academic institutions and other non-profit research organizations - the National Cancer Institute's (NCI) Rapid Access to Interventional Development, or RAID award.  This unique award, established in 1998, aims to support the swift movement of novel anti-cancer molecules and concepts like shepherdin from the laboratory to the clinic for proof-of-principle clinical trials.  The RAID application is submitted by a principal investigator who describes the scientific rationale for the project, documents his or her efficacy results to date and requests that specific preclinical tasks be performed.  The application is peer-reviewed, and if accepted, the NCI handles project management with input from the principal investigator.  No funding is awarded directly to the research or his or her laboratory, as is typical with traditional National Institutes of Health grants; rather, the work is provided through the NCI's contractor network, with the university owning all data generated.  Testament to the potential of shepherdin, Altieri's was the sole accepted proposal in this project cycle, chosen from some 40 applications.

"The RAID allows the NCI to select promising agents and develop them using their own facilities or alternative contractors with whom they have a relationship," said James P. McNamara, PhD, executive director of the Office of Technology Management and an expert in drug development who aided Altieri in crafting his winning application.  "In this way, they perform all of the tasks needed for an IND, or Investigational New Drug, at no cost of the university, saving UMass Medical School some $2 to $3 million in development and manufacturing expenses."

The ultimate conclusion of the RAID is a product, ready to bring into the clinic through an application with the FDA to begin Phase I trials with human subjects.  "When the RAID is concluded, we hope to have something in hand that is safe, that complies with FDA guidelines, that has gone through extensive toxicology testing is suitable for injection into humans,"  Altieri said.

In the initial stages of the studies, RAID resources will be used to conduct analytical assays in the test tube that establish stability and formulation of the agent.  "At some point, we need to put this compound into a vial," Altieri explained.  "We'll need to dilute it as a powder into saline or some other injectable solution to prepare for dispensing."  The product, therefore, must not precipitate in solution and be uniformly reproducible and effective among all lots manufactured.

Next, the NIC or its contractors will analyze something called pharmacokinetics.  Simply put, this term describes how the body distributes, absorbs, metabolizes and excretes a given drug; it also helps denote what concentration of the compound is needed to have a therapeutic effect.  Such findings help determine the set dosage and frequency of administration required for a pharmaceutical.  Finally, toxicology screenings are conducted in two animal models to gauge any potential side effects of the compound's prolonged use on main organs and tissues.  Once all three steps are complete, Altieri should receive a product back that is compliant with all rules and regulations of the FDA and can be given to humans in a Phase I clinical trial.

The one drawback to the RAID program is that it may take slightly longer to produce a viable compound for the clinic than if licensed to a pharmaceutical company - about two years in total.  However, Altieri is content with his choice to pursue the federal award.  "The RAID may take a little bit more time than what a drug company would need, bit it permits the institution and the originating investigators to be involved in the process."

Dr. McNamara added, "The RAID is a win-win in that it allows us to further develop technology and affords the investigator an opportunity to be involved in drug development.  More concretely, it increases the value of everything because we now have an investigational new drug, which we own, that is ready for the clinic and may spark more interest from investors."

Shepherdin represents translational cancer research at its finest, and reinforces Altieri's commitment to bring National Cancer Institute designation to the UMass Cancer Center.  Currently, 61 NCI-designated cancer centers across the nation receive such support that strengthens the integrative approach and the establishment of core facilities and joint programs, while ensuring the most rigorous, safe and compliant standards for clinical trials.  NCI designation helps ensure that the activity of a cancer center runs the gamut, spanning all aspects of cancer diagnosis, therapy, prevention and control.

It's this road from discovery to development about which Altieri is most passionate.  "Shepherdin is a personal and professional milestone in terms of achievement because, although it's one thing to find something interesting in the test tube and to publish your findings in a journal, it's another to develop a drug that has considerable promise."  He noted that given his medical background, he tends to looks at basic science research broadly; instead of focusing just on the molecular process, he sees the potential for the treatment of diseases as his greatest goal.  "I hope this fulfills that.  Whether shepherdin becomes a drug or not, who knows?  But regardless, this next step toward the development of a very promising compound that came out of our research lab is fantastic, and I'm thrilled with the prospects."

Dr. Tolcher agreed: "It's rare indeed to find an investigator who not only identifies a key target for cancer but also attempts to find a therapeutic to directly benefit cancer patients.  This represents the highest forms of discovery and translational research.  And, given that few such discoveries are funded by the RAID program each year, it further confirms that Dr. Altieri's peers and the National Cancer Institute recognizes this discovery at the highest level of science.