Turning Molecules into Medicine; The Role of the National Cancer Institute’s Developmental Therapeutics Program in Drug Development

Diagram of arteriole and cells

Diagram of arteriole and cells

The National Cancer Institute (NCI) is committed to the discovery and development of new and effective therapies for cancer. As a result, about half of the drugs used to treat cancer today are due to NCI’s efforts. The Developmental Therapeutics Program (DTP), within the Division of Cancer Treatment and Diagnosis (DCTD) is the drug development arm of NCI. Working with academic scientists, clinicians and commercial companies, DTP has contributed to the rapid development of drugs and therapies to improve cancer treatment.

The development of two therapies— the proteasome inhibitor, bortezomib (Velcade ®, Millennium Pharmaceuticals, Inc., Cambridge, Mass.), and E7389, a derivative of a naturally occurring substance from a marine sponge, called halichondrin B (Eisai Research Institute, Andover, Mass.) — illustrate the different roles NCI has played in helping promising agents move from the laboratory to the clinic.

In 1994, Julian Adams, Ph.D., was working for a small biotech company when his research group discovered a potent inhibitor of the proteasome, structures within cells that act like a garbage disposal for proteins. Inhibition of the proteasome causes proteins, which under normal circumstances would be destroyed, to accumulate in a cell and trigger cell death or apoptosis. Cancer cells are more sensitive than normal cells to the accumulation of these proteins and therefore, undergo apoptosis more rapidly.

Using the proteasome as a target for cancer treatment was initially met with skepticism, and Adams had to convince the scientific community that his idea was credible. He met with members of DTP in 1995 to discuss the further development of bortezomib. DTP scientists agreed that the proteasome was a novel therapeutic target and that further research was needed to validate this inhibitor was a viable therapy.

From 1995 to 1997, DTP funded animal studies that showed that bortezomib effectively inhibited the growth of cancer cells through targeting the proteasome. As a result, in 1998, DCTD agreed to provide support for Phase I testing of the compound.

“DTP improved bortezomib’s chances of moving to clinical trials quickly through our efficacy and toxicology studies and the development of a stable formulation for the drug,” said Joe Tomaszewski, Ph.D., deputy director of DCTD. “Through the combined experience of DTP and the Cancer Therapy Evaluation Program (CTEP), we were able to facilitate the process of clinical trials approvals and placement for this unique agent.”

In 2000, Phase I studies showed that bortezomib was effective against multiple myeloma, a cancer of the bone marrow. In a Phase II study involving 188 patients with multiple myeloma, 28 percent of the patients in this study showed improvement that lasted an average of one year. Based on these trial results, the FDA placed bortezomib on a fast-track for review and in 2003, bortezomib was approved as a new mechanistic class of cancer agent for treatment of patients with myeloma who had received at least two previous therapies and still had disease. An estimated 15,900 people were diagnosed with multiple myeloma in 2005 and more than 11,300 died of the disease. Bortezomib was the first new treatment approved for multiple myeloma in 10 years.

The route to clinical trial testing was quite different for E7389, a man-made derivative of halichondrin B, a naturally occurring substance obtained from sea sponges found in the South Pacific. In 1986, Japanese researchers isolated a small amount of a substance from the sponge Halichondria okadai that showed potent antitumor activity. This substance was named halichondrin B. Later, DTP conducted initial studies that showed this substance had potential as a cancer treatment.

In 1991, DTP researchers found that halichondrin B inhibits a cell’s ability to multiply by blocking the formation of microtubules (small, hollow, cylindrical structures) which are essential for cell growth . Halichondrin B binds to tubulin, a globular protein that is the main constituent of microtubules, and acts differently from other chemotherapy drugs that also affect these tubules, such as paclitaxel (Taxol ®).

Further study of halichondrin B was limited by the difficulty in obtaining sufficient amounts of the compound for testing. In 1994, DTP established an international collaboration with scientists in New Zealand to develop offshore cultivation of the sponges. Over five years, one metric ton of these sponges was harvested, yielding about 300 mg (1/100 th of an ounce) of the pure compound.

“The investment of DTP and the New Zealand government was pivotal in the continued study of this promising new compound,” said David Newman, D. Phil., acting chief, of the NCI Natural Products Branch, part of DTP. “We found that we could successfully cultivate and grow the sponge when needed.”

The amount of natural halichondrin B obtained from sponges, however, was so small that a more available source of the compound was needed. In 1998, DTP met with researchers from Eisai Research Institute, a Japanese pharmaceutical company. Scientists from Eisai had worked with Yoshito Kishi, Ph.D., Harvard University, who had successfully synthesized halichondrin B and discovered the active portion of this molecule. NCI had funded Kishi’s original research which led the way to the synthesis of several derivatives of halichondrin B. Scientists from Eisai offered two of the synthetic derivatives to DTP for comparison to the natural compound.

DTP scientists found that the synthetic derivative of halichondrin B, known as E7389 was significantly more effective antitumor agent than the natural product in animal models. As a result, E7389 was approved for clinical trials in 2001. Subsequent work by scientists from Eisai and in the laboratory of Mary Ann Jordan, Ph.D., University of California, Santa Barbara, recently demonstrated that E7389 has a novel mechanism of action in its interaction with tubulin. Early results from a Phase II trial conducted by Eisai, reported in December 2005, showed that 15 percent of breast cancer patients in that trial, whose cancer was resistant to other treatments, responded to treatment with E7389. NCI is planning several Phase II clinical trials to test the effectiveness of E7389 in treating a variety of tumors including ovarian, prostate, bladder, pancreatic head and neck cancers.

“The halichondrin B/E7389 story is a great example of how NCI collaborated with a foreign government and a foreign pharmaceutical company; everyone worked together to get this material into the clinic,” said Newman. “It is a lovely story, because it covers so many ways the NCI intervened to develop this new therapeutic agent.”

The mission of DTP is to facilitate the discovery and development of novel therapeutic agents for cancer treatment. This mission includes the rapid translation of new drugs and therapies from the laboratory to the clinic. DTP focuses on innovative approaches to deliver products that may be considered too risky by the private sector. These endeavors also may include working with other programs within DCTD to utilize novel regulatory and clinical trial pathways. DTP collaborates with investigators from academia, nonprofit organizations, and industry. There is no charge for DTP services or resources offered to collaborators, nor is there a requirement that collaborators form partnerships with DTP in developing a drug or therapy.

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Text Transcript

Scene 1

Cancer spreads by metastasis, which is the ability of cancer cells to penetrate into primarily blood vessels, circulate through the bloodstream, and then invade and grow in normal tissues everywhere.

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This process of forming new blood vessels is called angiogenesis, a normal process that also occurs in the absence of cancer.

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Tumor angiogenesis actually starts with cancerous tumor cells releasing molecules that send signals to surrounding normal host tissue. This signaling activates certain genes in the host tissue that, in turn, make proteins to encourage growth of new blood vessels.

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In this example inside the colon, tumor growth proceeds with angiogenesis.
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Inhibition of angiogenesis by drugs such as angiostatin have reduced the rate of spread (metastasis) by up to 20-fold.

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Without angiogenesis, tumor growth stops, and in the colon, what could have become a tumor remains a non-cancerous polyp.

Audio Clips

  1. Dr. Ernie Hawk, M.D., leader of NCI’s TRWG (Translational Research Working Group), discusses two aspects of translational research:

       ( Audio – Length: 01:43 – 1.59MB )

    Text Transcript

    Dr. Ernie Hawk, M.D., leader of NCI’s TRWG (Translational Research Working Group), discusses two aspects of translational research:

    “One [aspect of translational research] would be something like the discovery, you know, 35 or 40 years ago of the Philadelphia chromosome in patients with CML. And subsequently taking that observation on a chromosomal level into the molecular realm and discovering that it’s a translocation of the bcr and abl gene loci and the role of the abl oncogene in tumor angiogenesis. And subsequently the transformation of that knowledge into an effective inhibitor like Gleevec. That’s a very interesting approach for bench to bedside; it took decades, in that instance, and to make the translation yet nevertheless at the end of the day, now you end up with a drug that’s marketed and is prolonging the lives of vast numbers of individuals with CML.”

    “It’s kind of a classic example. Another one that I was more proximally involved in with is something like, again, you can trace these things back a long way. The role of prostaglandins in cancer development that was discovered back in the 70s subsequently identified that cyclooxygenase was an important enzyme. In developing those prostaglandins and discovering, through animal studies and observational studies and the population, as well as mechanistic studies, the role of cyclooxygenase in the development of a variety of cancers, in particular, intestinal cancer and then ultimately into randomized controlled trials that demonstrated drugs like aspirin or celecoxib are useful in inhibiting intestinal cancer.”

  2. Dr. Ernie Hawk, M.D., leader of NCI’s TRWG (Translational Research Working Group), discusses two aspects of translational research:

       ( Audio – Length: 00:43 – 681kb )

    Text Transcript

    Dr. Ernie Hawk, M.D., leader of NCI’s TRWG (Translational Research Working Group), discusses two aspects of translational research:

    “We on the TRWG have identified probably five pathways. One would be agent development that we just discussed. Another would be lifestyle modulation recommendations. So stopping tobacco, increasing physical activity, using dietary restrictions, etc. Another would be development of devices to assess risk. Another would be development of devices to intervene, so better biopsy probes or heat probes, that could be used to treat cancer or prevent it. So there are four or five different ways that we’re seeing as developmental things that get within translational science.”

Photos/Stills

NCI-designated cancer centers featured at the February 14, 2006 Science Writer’s seminar on the basics of clinical advances.

1. The Burnham Institute

The Burnham Institute


2. University of California San Diego/ Moores Cancer Center

University of California San Diego/ Moores Cancer Center


3. Salk Institute for Biological Studies

Salk Institute for Biological Studies

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