The Quest for Cancer Killers


By David Shook A molecule code-named STI-571 may someday be a cancer assassin. In clinical trials, it has been shown to selectively target cancer cells, with minimal or no effect on normal cells, giving scientists a glimpse of how medicine will fight cancer in the not-too-distant future.

Novartis (NVS) Oncology, the arm of the giant Swiss company that makes STI-571, isn't alone in developing such superselective cancer killers. While STI, which stands for signal transduction inhibitor, has shown great promise in fighting chronic myeloid leukemia, dozens of biotech and major pharmaceutical companies have made similar strides in different areas of oncology.

Who has the most promising cancer drugs, and how will they work? BusinessWeek Online turned to Dr. David Parkinson, Novartis Oncology's vice-president and chief of clinical trials, based in East Hanover., N.J., for some answers. A former chief of the National Institute of Cancer's Investigational Drug Branch, Parkinson has an authoritative view of this pioneering field. And he's not bashful about identifying developments in his field -- from others as well as from his company -- that he believes may carry the most hope in the next few years. Parkinson spoke by phone with BusinessWeek Online Reporter David Shook on Jan. 22. Here are edited excerpts of their conversation:

Q: What are the prevailing themes in oncology-drug development today?

A: I head up global clinical research and development for Novartis Oncology, which is now a separate unit focused on one specialty area. The reason we've done this is that oncology is very different from the mass-market development and straightforward clinical trials for so many other diseases. In cancer, our understanding of the biology is accelerating but is still relatively unclear. We're all trying to develop small molecules, engineered proteins, or antibodies to interfere with putative targets [that appear to play a role in cancer]. The issue is, what is the relevance of all these new putative targets? How do we validate them? How do we handle the clinical trials? What end points do we choose?

It used to be that oncology development entailed very straightforward thinking. We thought that agents went right to the DNA or RNA [in cancer cells]. We wanted big tumors to become smaller tumors. That response was the end point expected. Now there are so many more questions about how we choose targets and design clinical trials. Where do we put our resources? This can be perilous from a risk-management point of view. But it also is associated with huge opportunities. And right now, we're sitting on the edge of some agents that can really cause excitement in cancer treatment.

Q: What is Novartis' leading candidate in the labs?

A: Glivec, our STI agent, is causing a lot of excitement because there we understand the biology very well. We've developed a molecule that interferes with the cancer, mediating cellular activity. The target we're talking about is a protein whose role in normal physiology is still largely undefined. But we know that when the molecule is turned on inappropriately, you end up with chronic myeloid leukemia. And we know that when you interfere with that process, you can treat the cancer.

Q: Is this similar to other new products on the market, such as Genentech's (DNA) Herceptin for breast cancer?

A: It is similar to Herceptin in the sense that both companies have identified biologically relevant targets associated with cancer. In their case, they're using the herceptin antibody. In STI's case, we're talking about using a small molecule [which means it can be taken as a pill rather than having to be delivered intravenously, as antibodies and other large-molecule-based treatments must]. Therefore, we may be able to treat targets anywhere in the cell. Also, theirs is different in that, by itself, it has quite unremarkable clinical activity. The value appears to be in combination with cytotoxic drugs [used in conventional chemotherapy].

Q: Is the idea behind STI-571 that it may eliminate the need for more traditional chemotherapy that so often has painful and exhausting side effects for patients?

A: Our best guess so far is that STI may eliminate the need to use interferon, and it may add greatly to the value of chemotherapy in more acute stages of the disease.

Q: What else is out there that could play an integral role in fighting cancer?

A: In terms of small molecules, I think what we're going to see [some] development of substances over the next two to three years that inhibit tyrosine kinases, which are enzymes known to help initiate cancer-cell reproduction and growth. One example of this type of inhibitor is Iressa, an epidermal growth factor inhibitor from AstraZeneca (AZN).

Similarly, at Novartis we have what's called a vascular endothelial growth factor inhibitor, or anti-VEGF, in development. That's an anti-angiogenesis agent. [The idea behind these drugs is to starve a tumor by cutting off its blood supply or otherwise block its growth.]

Then there's Sugen Inc., now a part of Pharmacia (PHA), which has several very interesting products in development along these lines. There are others, including OSI Pharmaceuticals (OSIP), which has an EGF inhibitor.

Q: Are these biotech companies that we should keep an eye on?

A: These are companies that may have very important products in oncology in the next two to three years. Pfizer (PFE), the largest drugmaker in the U.S., also has an interesting molecule that inhibits the EGF receptor. Pfizer took ownership of this potential drug when it acquired

Warner-Lambert last year.

Q: O.K., so you've got these so-called tyrosine kinase inhibitors poised to fight several forms of cancer. What else? Where does Idec Pharmaceuticals' (IDPH) monoclonal antibody Rituxan, one of the industry's hottest new cancer products, fit in, for example? (See BW Online, 12/28/00, "Why Idec May Be a Bit Too Healthy.")

A: Here you've got this new class of antibodies that go after relevant targets. This includes Rituxan as well as Herceptin. Then you have antibodies like ImClone Systems' (IMCL) molecule 225, which hits the same target as AstraZeneca's Iressa but is an antibody [rather than a small-molecule-based drug]. Then you have Genentech's anti-VEGF antibody. There are others, and there are relative pros and cons to each of these potential drugs. But they have been among the first to make a big impact.

Q: Are there other oncology groups you can identify within the industry that may lead to important drugs soon?

A: We are starting to see agents that affect gene expression -- small molecules which affect gene transcription. There is a lot of work in this area from many different companies. It's best to think of it this way: Cancer is really a disease of disordered gene expression. So to the extent that you can shut down gene activity or turn on suppressed gene activity, you have the ability to turn on and off patterns of gene expression. This is like hormonal therapy. Several companies are studying disordered or suppressed gene expression as it relates to cancer.

Separately, there is a group called cyclin-dependent kinases. These are enzymes which are very important in regulation of the cell cycle. That right now is a hot topic in oncology, and Aventis (AVE) is a major player in that field.

Q: There seems to be so many companies pursuing hundreds of different forms of cancer treatment. Will we finally see some form of cure for cancer in the next few years?

A: As we learn more about the biology of cancer, we are appreciating that the major common tumors such as breast or colon cancer, contain distinctly different biological subtypes. I believe that the next few years will see dramatic improvements in the treatment of particular subtypes, but that the pattern will be continuous incremental developments, rather than a single giant leap forward. I do believe that cancer treatment will improve significantly over the next several years, as a result of new biology, and new drug development technology. Shook covers the biotech industry for BW Online in New York >


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