University of Michigan Comprehensive Cancer Center: Leading the Way in Targeted Therapies Cancer Care

University of Michigan Comprehensive Cancer Center

It was 1986 when University of Michigan (U-M) regents designated a cancer center program. In May of 1997, a nine-story building was opened to house clinics and laboratories devoted to both cancer and geriatrics. Design of the facility was based on the then-radical premise that everyone involved in the fight against cancer should be working together under a single roof.

Today, as a National Cancer Institute-designated comprehensive cancer center and a founding member of the National Comprehensive Cancer Network, the U-M Comprehensive Cancer Center in Ann Arbor offers diagnostic, treatment, and support services while serving as a model for other branches of the U-M Health System and for academic peer organizations nationwide. Nearly 150 cancer physicians from eight departments collaborate in the center’s multidisciplinary clinics, streamlining care and maximizing communication by bringing together nurses, mid-level providers, and support staff grouped into teams, principally by tumor type.

Among the most noteworthy of the institution’s many programs designed to facilitate the translation of research findings into meaningful advancements in patient care are the Ravitz Foundation Phase I /Translational Research Center and the U-M Cancer Center’s stem cell research program.

Ravitz Foundation Phase I/Translational Research Center

Opened in 2008, the Ravitz Foundation Phase I/ Translational Research Center (TRC) is a specialty unit dedicated to phase I translational research and focused solely on targeted therapies. By harnessing U-M Cancer Center laboratory research, evaluating novel therapies at the earliest stage in the FDA’s regulatory process, and expediting their translation from bench to bedside, U-M scientists and clinicians are offering new hope to patients who would otherwise have no options.

Located within the university’s cancer center, the TRC is designed to enable specialized patient monitoring and, through its laboratory, to offer a wide range of services aimed at assessing the biologic impact of potential therapies used in the clinic.

David C. Smith, MD

With associate director of Translational Research Moshe Talpaz, MD, and TRC clinical director David C. Smith, MD, at the helm, the phase I program offers a comprehensive array of translational research resources not only to U-M faculty, but also to investigators at other institutions, and to pharmaceutical and biotechnology companies.

Among the most exciting benefits of the program is the potential for streamlined regulatory and contractual processes. When an investigator initiates a new study with the TRC, the protocol review process—much of which is managed electronically— is handled concurrently with study contract-services negotiations, enabling completion in approximately eight to 12 weeks.

A Pioneering Approach

U-M leaders are pleased with the way the TRC is developing.

“We initially expected to handle roughly 10 phase I trials per year, but we’ve actually exceeded those expectations, and currently have 13 trials in the pipeline,” said Smith, noting that more than 100 patients were enrolled in trials during the second full year of operation, and that additional patients are awaiting trial openings.

Smith was quick, however, to explain that the focus of the program is not to expand, but to build an infrastructure that will provide the highest-quality data. Central to the ability to generate such data, and to demonstrate the integrity and validity of study findings, he noted, are the TRC’s dedicated regulatory and data-management staff.

Another intriguing aspect of the program’s growth, Smith said, is its technique for matching patients to trials, which is about to become more complex.

“We’re looking beyond matching a patient to a given trial based solely on generic phase I eligibility,” he said. “Instead, the next step is to match patients to trials according to genetics—a concept we’re just about ready to launch with an ongoing program that will involve biopsying, and subsequent deep sequencing, of the tumors of patients enrolled in phase I trials. Ultimately, patients with several types of cancer may participate in a single phase I trial. Once researchers determine the best dosage of a given drug, they’ll use what they learn to help develop broader studies.”

Although convincing patients to undergo biopsy when there’s no guarantee of a drug match might, for some, be a tough sell, the effort will be worthwhile for U-M, Smith said, because having tumor genotype or mutation cohorts will allow researchers to examine mechanistic pathways and determine what, if anything, alters them.

“While a number of centers are looking at figuring out how to identify genetic abnormalities, our focus on deep sequencing really does set us apart,” he said.

Even so, Smith called for a degree of caution when envisioning the level of personalized treatment that can realistically be expected.

“We can’t anticipate that every patient will have a tumor profile, and that those profiles will, in turn, automatically translate into finding the optimal treatment for each patient,” he said. If that were possible, Smith added, the TRC would face the challenge of screening an enormous number of patients for genetic abnormalities.

Already a leader in that field, U-M Cancer Center is exploring treatments that target cancer stem cells, and have already begun testing these concepts in the phase I program. Organized teams of U-M scientists are looking at stem cells in virtually every cancer type, including adrenal, breast, colon, head and neck, lung, melanoma, myeloma, pancreatic, prostate, thyroid, and leukemia.

Max S. Wicha, MD

“We currently have 15 different labs working on cancer stem cells and are meeting regularly to share information,” said Cancer Center director Max S. Wicha, MD, a leading cancer stem cell researcher.

It was U-M researchers who were the first to discover cancer stem cells in a solid tumor, finding them in breast cancer in 2003. U-M scientists have gone on to become the first to identify stem cells in head and neck, pancreatic, and ovarian cancers. U-M is conducting or has completed nine trials looking at targeting cancer stem cells—more such trials than any other center in the world, Wicha said.

To date, breast and pancreatic cancer are the best-studied malignancies with regard to stem cells, and some extraordinary findings are coming to light.

“We already know that some of the key signaling pathways in breast cancer are intrinsic to the cell, but we’ve now discovered that others involve interaction with the stem cell microenvironment,” Wicha said. “In the animal model, dying breast cancer cells increase their secretion of interleukin 8 (IL-8) when treated with conventional chemotherapy agents; in other words, chemotherapy actually stimulates the cancer stem cells to reproduce.”

In response to this finding, U-M and Philadelphia’s Fox Chase Cancer Center have initiated a trial of an IL-8 receptor inhibitor, developed as an antirejection agent, in patients with advanced breast cancer who will be treated with the agent after conventional chemotherapy.

In the area of pancreatic cancer, two trials are aimed at targeting pancreatic cancer stem cells by inhibiting the Notch and c-Met pathways.

Also in the works is the development of animal models, in which primary xenografts generated from patients in the operating room are implanted into immunosuppressed mice. “These xenografts are more biologically reliable than established cell lines,” Wicha explained.

University of Michigan (U-M) Comprehensive Cancer Center Timeline

1986

1991

2003

2006

2007

U-M regents designate a cancer center program.

U-M is named a “comprehensive” cancer center by the NCI.

U-M researchers publish the first paper identifying cancer stem cells in a solid tumor, having found them in breast cancer. Researchers believe these cells are resistant to current chemotherapies and radiation.

The building opened in 1997 becomes totally devoted to cancer treatment and research.

U-M researchers are the first to identify stem cells in pancreatic cancer, and in head and neck cancer.

1988

1997

2003

2005

2008

The National Cancer Institute (NCI) gives U-M a cancer center designation.

A nine-story building is opened to house clinics and laboratories devoted to cancer and geriatrics.

Non-Hodgkin lymphoma treatment Bexxar, conceived of and developed by U-M researchers, is FDA-approved.

U-M researchers identify a “gene fusion” that occurs in about half of prostate cancers. This becomes the building block for developing personalized, molecularly targeted prostate cancer treatments.

The Ravitz Foundation Phase I/ Translational Research Center opens, providing a dedicated resource for evaluating novel cancer therapies at the earliest stage in the FDA’s regulatory process.

Critical Partnerships

U-M is conducting some of its stem cell research in partnership with the pharmaceutical and biotechnology industries, giving the institution access to the newest therapies and the tools necessary to serve as a site to test such agents.

In addition to working with Fox Chase, U-M will participate in a group of trials funded by a grant from Susan G. Komen for the Cure in collaboration with Karmanos Cancer Institute in Detroit; the Translational Genomics Research Institute and the Van Andel Research Institute in Grand Rapids; and Baylor College of Medicine in Houston. In those trials, agents targeting stem cell pathways will be used in women with triplenegative disease. Core biopsies obtained before and after treatment, along with complete cancer stem cell analysis, will be used to identify factors related to sensitivity and treatment resistance.

To explore other agents that target stem cells, Wicha and his collaborators have launched OncoMed, a California-based biotechnology company. To date, the company has developed three such agents (two Notch inhibitors and one anti- Wnt agent) and will seek to determine whether the potential treatments can successfully target cancer stem cells.

U-M is also collaborating with AstraZeneca’s MedImmune, a world leader in the development of biologic therapies, on translational and preclinical research projects.

These partnerships add a unique dimension to U-M’s long-standing commitment to a collaborative approach to research, providing a critical piece in the puzzle that is necessary to expedite the move of novel therapies from bench to bedside.