Life Raft gleans facts at oncology meeting

By Norman Scherzer Life Raft Group Executive Director

Jerry Call, our Science Team Leader, and I attended the Connective Tissue Oncology Society meeting held Nov. 1-2 in San Francisco, Calif. CTOS is an international organization of physicians specializing in the family of cancers called sarcomas, of which GIST is a part.

For those of you who do not know Jerry Call, let me tell you that he is one of the smartest people I know. Jerry is a self-taught scientist with the incredible ability to understand and articulate complex scientific issues affecting GIST.

The following report is based upon a combination of our notes, recollections and meeting abstracts. It is subject to human error and should be read with appropriate caution. We have tried to achieve a balance between clarity and scientific detail, but have not always succeeded.

I had the opportunity to make a 20-minute presentation to the conference on the experience of the Life Raft Group. If you would like a copy, please write to me privately (nscherzer@liferaftgroup.org). You will need Microsoft PowerPoint to open it; it is basically the same as the one I gave in London.

CTOS is a relatively new organization and is, to the best of our knowledge, the only medical organization focusing upon sarcomas, It is poorly funded and loosely organized, but getting stronger in such areas as scientific exploration and collaboration. I have asked the secretary of the CTOS Board of Directors, Dr. Robert Benjamin of M. D. Anderson Cancer Center in Houston, Texas, U.S.A., for their membership list and permission to post it to the Life Raft Group Web site. Dr. Benjamin seemed agreeable. If we are successful, this will give us an international directory of sarcoma specialists, something GIST patients have long sought.

The agenda of the meeting, including its posters (posters are scientific exhibits set up in a separate room for meeting participants to review) was broad based and only a very small part of it focused upon GIST or Gleevec. The topics were often tough for the layperson to follow (even one as bright as Jerry). An example: “Antisense Inhibition of Hyaluronan Synthase-2 in Human Osteosarcoma Cell Line, Mg- 63, Inhibits Hyaluronan Retention and Tumorigenicity of the Cells.” The talks began at 7:30 a.m. and ended late in the day.

The general sarcoma highlights that may have some relevance to GIST included:
● A report demonstrating the reliability of ultrasonagraphy in detecting chest wall sarcomas (Italy).
● A report that PET scanning is not useful for detection of lung metastases (U.S.A.).
● A report that centralization of treatment in specialty centers improves survival, local control and patient care (U.K.).
● A report that a positive surgical margin is associated with a higher risk of local relapse but not necessarily with survival (U.S.A.).
● A report comparing doxorubicin and ifosfamide in treating advanced or metastatic soft tissue sarcomas, concluding that for the majority of patients for whom singleagent chemotherapy is appropriate, doxorubicin remains the drug of choice (Belgium).
● A report that for radiation treatment of sarcomas of the pelvis, proton beam technology is predicted to yield a higher proportion of patients who are rendered tumorand complication-free (U.S.A.). Note: this technology is quite expensive and not available at most medical centers.
● A report that adjuvant therapy with Gleevec may be useful in c-kit negative soft tissue sarcomas where there is an activated form of AKT. AKT is a cytoplasmic serine/ threonine kinase, which is a common target for RTK phosphorylation, thought to be alternative targets for the RTK inhibitor, Gleevec).

There was little new presented on GIST. The trials continue and preliminary reports are that the activity of Gleevec in GIST is long lasting. We would caution that these reports are based upon the one-year mark.

Most of what we learned about GIST took place in informal sessions with a number of key sarcoma experts, including Dr. George Demetri of Dana-Farber Cancer Institute in Boston, Dr. Margaret von Mehren of Fox Chase Cancer Center in Philadelphia, Dr. Robert Maki of Memorial Sloan-Kettering in New York City, Dr. Mary Lou Keohan of Columbia-Presbyterian Medical Center in New York City and M.D. Anderson’s Benjamin (there were many more we had brief interactions with). I continue to be pleased and impressed with the candor and cooperation that these experts accord to the Life Raft Group.

New drugs

RAD: The new Novartis drug called RAD (RAD001) appears to be on track (though these tracks can never be fast enough for GIST patients) and has cleared the federal regulatory pre-clinical-trial hurdles. It is now awaiting approval from Dana-Farber’s review board and our best guest is that trials for his new drug are about two months away in the U.S. (probably at Dana-Farber), but are getting underway now in Belgium.

This drug targets a component of the mTOR (mammalian target of the drug Rapamycin) pathway, which is one component of the AKT pathway (a downstream pathway in KIT signaling). Pre-clinical experiments (in vitro experiments in chronic myelogenous leukemia) have suggested that targeting downstream components of Bcr- Abl, including the mTOR pathway, have resulted in greater effectiveness than Gleevec alone. So this drug would be given in combination with Gleevec.

Note’s Jerry Call: “An existing drug, Rapamycin, already targets this pathway. Analogs of Rapamycin are being developed. I believe that the reason an analog of a drug might be developed (not necessarily in direct relation to GIST or Gleevec interests) is that it might be either more efficient than the parent drug, and/or less toxic than the parent drug. In theory, it would be possible that Gleevec and Rapamycin could be given together in an off-label indication, if you could find a doctor willing to do that. Toxicities or effectiveness of this combination are unknown.”

One Life Raft Group GIST patient is being treated by his physician with a combination of Gleevec and Rapamycin. It is too soon to evaluate its effectiveness.

Genasense: Talk is underway with the biopharmaceutical company Genta about a trial combining Gleevec with Genasense. Genesense works by inhibiting the production of Bcl-2, a protein made by cancer cells that blocks chemotherapy- induced cell death. As a result, it may enhance the effectiveness of treatments like Gleevec. It is beginning clinical trials for Gleevecresistant chronic myelogenous leukemia. Remember that this drug is just in the discussion stage: there is no clinical trial on track yet for GIST.

Note by Jerry Call: “This antisense drug reduces the amount of Bcl-2 mRNA (part of the instructions to manufacture the Bcl-2 protein). In theory, this drug should tip the balance between pro- and antiapoptosis proteins towards more apoptosis (cell death). Trials with this drug have been conducted in melanoma, however, I am not aware of the results, other than it did seem to reduce Bcl-2 protein levels.”

Levels of cooperation (or at least intent to cooperate) seemed high at the meeting between Europeans, Canadians and Americans. There was, however, a general concern regarding the difficulty in overcoming government “over-regulation.” Many medical professionals feel that government has swung so far towards the side of protecting “patient rights” that it is very difficult to get things done. In particular, it is difficult to get much help from the National Cancer Institute due to bureaucratic obstacles, and it is difficult for the U.S. to collaborate/ share trials with Europeans (and presumably Canadians as well).

SU011248: The new Sugen drug SU011248 has been in phase l clinical trial at Dana-Farber for several months. Preliminary information (take this information with great caution; this is a phase l trial designed to measure drug safety levels, not effectiveness) is that a significant number of GIST patients not responding to Gleevec do respond to this drug in combination with Gleevec. It would be reckless at this point to assign a public statistic to the term “significant.” A new trial is to begin shortly at Memorial Sloan-Kettering. One is also expected in Canada, but we were unable to get any information about start dates there.

There is also a note of concern raised by the fact that Sugen has been bought by Pharmacia, which in turn has been bought by Pfizer. The new research and marketing bureaucracies may change the focus of interest in certain drugs.

We found that the most cutting edge information is often best obtained via behind-the-scenes professional networking. We are getting new reports of GIST resistance to Gleevec; not enough to panic, but sufficient to galvanize our energies to, 1) identify new, existing drugs and compounds (we cannot wait the 10-plus years it takes to develop brand new drugs) and, as important, 2) to influence the decisions of drug companies in bringing new drugs to trial and to market. I was concerned, for example, that Novartis was not represented at the CTOS meeting and I am following up to find out why.

Our bottom line issue with every researcher must be: what are you doing to overcome current and potential resistance to Gleevec? It is becoming increasingly clear that GIST will ultimately be treated by a combination of drugs, not just Gleevec alone.

We must make sure that these arrive on time.