AACR reports on drugs with GIST possibilities

Some emerging drugs ready for clinical trials

Editor’s note: Jerry Call attended the 95th annual meeting of the American Association for Cancer Research held March 27-31 in Orlando, Florida. This is his report on the handful of sessions (out of 250-plus) that he was able to attend. Jerry adds that he is a layperson with no formal medical or scientific training.

By Jerry Call
Science Coordinator, Life Raft Group

The good news emerging from the AACR meeting is that researchers are pursuing many treatment avenues that could work on GIST, and some of these new drugs are or will soon be in early clinical trials.

The treatment strategies represented at the meeting can be divided into three main categories. The first were highly specific treatments aimed at very specific targets. These include small molecule inhibitors (such as Gleevec), antisense drugs, and monoclonal antibodies. The second category consists of newer types of chemotherapy aimed at rather broad targets. This class appeared dominated by three main types of drugs: heat shock protein 90 (hsp90) inhibitors, proteasome inhibitors, and histone deacetylase inhibitors. A third category of less concern to GIST patients was the more traditional treatments such as traditional cytotoxic chemotherapy and radiation. GIST is relative immune to such treatments.

Small molecule inhibitors (such as Gleevec) are probably the best representatives of the highly specific treatments. Gleevec is a small molecule “tyrosine kinase” inhibitor. It inhibits KIT, PDGFR, as well as various forms of ABL (such as Bcr-Abl). Many of the tyrosine kinase inhibitors inhibit several different kinases.

As targets are identified, researchers seem to be able to make drugs that more potently inhibit the target. Two examples of this were in drugs that inhibit KIT/Bcr-Abl, and STAT-3 (KIT is implicated in GIST, as is STAT3, to a lesser degree). Aberrant Bcr-Abl signaling is the primary cause of chronic myelogenous leukemia (CML).

Gleevec is the treatment of choice for CML and metastatic GIST. A new drug being developed by Bristol- Myers Squibb was reported to be 100 to 1,000 times as potent as Gleevec at inhibiting Bcr-Abl (this does not mean that it would be 100 to 1,000 times as effective). Researchers at Moffit Cancer Center working on drugs that inhibit STAT3 signaling have achieved a 10-fold increase in STAT3 inhibition in one year and expect another 10-fold increase in another year.

The point: new drugs that inhibit old targets (perhaps more potently) appear to be one option for better treatments.

The new Bristol-Myers Squibb drug, BMS-354825, inhibits Bcr-Abl as well as KIT and PDGFRA signaling, according to Frank Y.F. Lee, Ph.D., senior principal scientist with Bristol- Myers Squibb. After his presentation, I spoke to Lee with Penny Duke, a member of both the Life Raft Group and GIST Support International. Lee told us that plans are under way for a phase I trial of BMS-354825 for patients with solid tumors. This trial will be at Dana-Farber Cancer Institute in Boston. It remains to be seen whether this drug, or another new KIT/ PDGFRA inhibitor such as AMG-706, will be effective in GIST.

Other KIT or PDGFRA inhibitors we were already aware of include the Novartis drug PKC412. According to Dr. Jonathan Fletcher, PKC412 may target KIT and PDGFRA differently from Gleevec, especially the kinase domain mutants typically resistant to Gleevec. My impression: the new PKC412 plus Gleevec trial at Oregon Health & Sciences University in Portland may be a good choice for GIST patients with PDGFRA mutations that are resistant to Gleevec.

While KIT remains the primary target in GIST (with PDGFRA the primary target in GISTs with PDGFRA mutations), several new abstracts were presented on other GIST targets.

Wei Shen of Fox Chase Cancer Center presented a poster of the effects of a novel STAT3 inhibitor, JSI-124 (Cucurbitacin I) in GIST cells. In the past six months or so, several articles have described the importance of STAT3 signaling in GIST, while noting that Gleevec does not always inhibit STAT3 signaling.

The authors of this poster tested JSI-124 on GIST882 cells and found that it inhibited cell proliferation and induced apoptosis (cell death) in this cell line at clinically achievable drug concentrations. The authors concluded, “These studies suggest that JSI-124 may be an alternative or complementary drug for the treatment of primary and refractory GIST.”

Dr. Annette Duensing of the University of Pittsburgh, while working in the Fletcher’s lab at Dana-Farber, found that protein kinase C theta (PKC theta), was highly activated in GISTs. They found that PKC theta was activated not only in GISTs with c-kit mutations, but also in GISTs with PDGFRA mutations (although at about 50 percent lower levels). Duensing and her colleagues found that “PKC theta was strongly phosphorylated in all GISTs at Thr538 and Ser676, and the phosphorylation at both these residues was two- to five-fold greater in the GISTs than in Jurkat cells and normal thymus (cells considered to have high PKC theta activation). Treatment of the GIST430 cell line with the PKC theta inhibitor Rottlerin (3 µM) led to inhibition of PKC theta and AKT phosphorylation, and induction of cell death.”

I believe that Rottlerin is more of a lab chemical than a drug that will be developed for patients. The authors conclude, “PKC theta expression is characteristic of GISTs, and of potential diagnostic utility, particularly in KIT-negative GISTs. PKC theta is constitutively phosphorylated (activated) in GISTs and — given its role as a positive regulator of cell survival in other cell lineages — might represent a novel therapeutic target in GISTs.”

While not specific to GIST, a session titled “Sarcoma Diagnosis and Treatment” presented a few new pieces of information about GIST. Speakers included Dana-Farber’s Fletcher, Dr. Lee J. Holman from the National Cancer Institute, Dr. Brian O’Sullivan from Princess Margaret Hospital, Toronto, and Dr. Matt Van de Rijn of Stanford University Medical Center).

Van de Rijn has identified a novel marker for GIST that may be more specific than c-kit. This marker which Van de Rijn has named “dog1” reacts with KIT-negative GISTs as well as KIT-positive GISTs (about 97 percent of GISTs are “KIT positive”). Further work is needed to validate dog1 as a marker in GIST.

Fletcher noted that one major challenge (and opportunity) is that there seems to be a greater-than-expected heterogeneity (variation/subclones in tumors/tumor cells) in GIST. He said that by using several drugs together, researchers hope to make progress.

Other downstream KIT and PDGFRA targets include the PI3K/ AKT pathway (including mTOR) and the MAPK pathway. Approved drugs (Rapamycin) and those in clinical trials (RAD001 and others) target mTOR. Several new drugs that inhibit PI3K and AKT appear to be in preclinical development. One new tyrosine kinase inhibitor, BAY 43-9006, inhibits RAF, which is in the MAPK pathway. It is conceivable that this drug may one day be useful in GIST.

NEWER CHEMOTHERAPIES AIM AT BROAD TARGETS

This group seems to be dominated by three main targets. The general strategy of this group seems to target the processes (or “machinery”) that cells depend on, the theory being that cancer cells may be more dependent on these processes than normal cells.

The first of these targets is heat shock protein 90 (hsp90). Hsp90 is one of the most abundant proteins in most cells, accounting for 2 to 4 percent of total cell protein. It is required for refolding of proteins and participates in maturation of some proteins (AKT and others).

Treatment with hsp90 inhibitors results in the degradation of some proteins including: HER2, MET, RAF kinase, Steroid receptors, and AKT. In addition, KIT protein (as reported last year at ASCO) may also be degraded by hsp90 inhibitors. This includes types normally resistant to Gleevec, such as kinase domain mutations.

Hsp90 degraded proteins are “marked” with “ubiquitin”. Proteins marked with ubiquitin are then degraded by a “machine” called a proteasome. Proteasomes serve a housekeeping function in the cell. As proteins are no longer needed, they are degraded by the proteasome. Proteasome inhibitors are second in this class of drugs aimed at broad targets.

The third target in this general class is histone deacetylase. A histone is a basic protein found in the nucleus of a cell. This protein, found as a complex with DNA, is specifically found in chromatin and chromosomes, and may function as a repressor of gene transcription.

Because histones are involved in transcription, one of the first steps in cell division, and cancer is caused, generally, by uncontrollable cell replication, they are targets for cancer research.

All three of these new, general acting chemotherapies have shown some invitro (test tube) activity in CML cells, either alone or in combination with Gleevec, or in some type of combination of the three inhibitors. Of these three types, I am only aware of an hsp90 inhibitor (17-AAG) being tested for inhibition of KIT. This was an invitro test with mast cells that expressed a KIT mutation that would normally be resistant to Gleevec.

The authors concluded “17-AAG may have a role in the treatment of other diseases where c-kit plays a crucial role in pathogenesis, including GIST, mast cell leukemia, some types of acute myelogenous leukemia and testicular cancer.”

It seems possible that one or more of these general chemotherapies, or a combination of them, might be useful in GIST (perhaps in combination with Gleevec or another KIT inhibitor). One concern with this group is that proper drug sequencing will probably be very important or critical, and would have to be determined for each combination.

Velcade is the only approved proteasome inhibitor that I am aware of. It is approved for Multiple myeloma.

The hsp90 inhibitor that is furthest along in trials is probably 17-AAG. This drug has some drawbacks including poor solubility.

At least two newer hsp90 inhibitors were reported at AACR. One was 17DMAG, which is water soluble, orally bioavailable, and does not appear to undergo metabolism to toxic species. In other words, this drug is an improvement over 17-AAG. Phase I trials are just starting (at the University of Pittsburgh, I believe). The other is PU24FCl (reported by Memorial Sloan-Kettering Cancer Center in New York). A representative of the hsp90 inhibitors that exhibit in vivo antitumor activity, PU24FCl, has anti-tumor effects on all tested cancer cell lines.

Histone deacetylase inhibitors represent one other class. Novartis (LAQ824) and others are developing histone deacetylase inhibitors.

AACR is the world’s largest professional organization devoted to cancer research. This year more than 15,000 participants gathered to discuss some 6,000 abstracts and to hear more than 250 presentations on new discoveries in cancer research.