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AACR 2002 MEETING REPORT
Dr. Hirendranath Banerjee
Elizabeth City State University

Students in our lab are working on the role of tyrosine kinase inhibitors and other novel therapeutic agents on treatment of the brain cancer Astrocytoma. Thus visiting the AACR 2002 annual meeting at San Francisco, CA was very fruitful for them in experiencing and learning about the current progress in cancer therapy, diagnosis and epidemiology. The following is a brief description of the meeting and coverage of the major events.

A major theme at the meeting was the elucidation of molecular reasons why combination chemotherapy has proved so effective, and why blockbuster drugs are unlikely to provide cures single handedly. Cancer proceeds by numerous pathways, and more than one must be blocked to conquer it.

Downgraded from the miracle drugs they were predicted to be, angiogenesis inhibitors will soon be an effective adjuvant therapy to treat cancer, used in combination with other therapies, leading experts agreed at the conference. The drugs show promise in lung cancer, but reaching their full potential depends critically on adequate patient profiling, which has yet to exist, they said.

Researchers have only recently discovered the involvement of hematopoietic and endothelial stem cells in tumor growth. Tumors recruit bone marrow-derived endothelial and hematopoietic progenitor cells by two separate mechanisms, each of which must be blocked to inhibit tumor growth, Cornell University researcher Shahin Rafii said. The new paradigm creates several new targets for therapy, and a new mechanism for detecting cancer.

Angiogenesis legend Judah Folkman revealed to a packed audience that a simple variation in the classic corneal assay allows disassociation of blood vessel formation from the development of lymphatic vessels. Based on the assay, he said, vascular endothelial growth factor-A (VEGF-A) mediates blood vessel formation, while VEGF-C and D promote lymphatic vessel formation.

As with the angiogenesis inhibitors, drugs - like anti-BCL2 compounds - designed to target only one branch of the apoptosis pathway are likely to fail in hard-to-treat acute myeloid leukemia cases, researchers reported in the late-breaking abstracts session.

Among the outstanding successes in cancer research is Gleevec, the product of rational drug design. Few if any similar drug targets in cancer have delivered the same level of effectiveness, and researchers are now learning from the initial Gleevec clinical trials. It is very likely that all of the new molecular-target based drugs will work best in combination.

So, very likely, will therapeutic antibodies, after more than 20 years in development, they are finally producing promising clinical results in cancer treatment. But significant challenges remain in designing these antibodies for optimal use in humans.

Results of a very preliminary clinical trial suggest that adoptive T-cell therapy may prolong the lives of patients with metastatic melanoma by slowing the disease. A scientist involved in the study called it "the best example" of ex-vivo expanded T cells for cancer therapy.

Another approach involves attacking tumor cells' ability to sense nutrients. Imitating a bacterium's natural weapon against fungi, several independent teams of researchers are designing drugs to fool tumor cells into thinking they're starving, and provoking them to shut their metabolic machinery down.

In a related development, one of the first studies of senescence in human cancer supports the theory that chemotherapy may fail because tumor cells under cytotoxic attack become passive-aggressive. They stop growing, but they do not die, continuing to send "grow" messages to cells.

Right behind the holy grail of curing cancer is the goal of early, reliable, easy detection. Several important talks revealed advances that may lead to earlier detection, better diagnosis, or early warnings of advanced disease.

For example, two groups of researchers discussed the development of proteomics-based blood tests for ovarian cancer saying the advance could be critical, as there is no good noninvasive test at present.

A new approach to locating cancer-risk genes has identified a novel low-risk gene apparently involved in breast cancer. Adding this information to analyses that include the known BrCA genes generates a normal risk curve that, unlike the one predicted using the two BrCA genes alone, resembles the real epidemiological situation.

German researchers have also identified a mutation that may be linked to the progression of head and neck squamous cell carcinoma. While the mutation is not responsible for the cancer, it may explain why the disease accelerates rapidly in some patients, but not in others.

Not surprisingly, the fruits of research into the genome were very evident. Because as much as 80% of the human genome is composed of ancestral blocks of DNA that have remained intact over time, using such data on genetic variation and single nucelotide polymorphisms could improve the power of SNP association studies, experts said.

Also, a preliminary study of the effects of the antidepressant bupropion on smoking cessation may help identify which smokers are genetically inclined to be responsive to drug therapy in helping them kick the habit, epidemiologist Caryn Lerman reported.

At the same time, ethicists cautioned, progress in gene identification is outpacing our ability to construct sound social policy about genetic testing.

Several presentations unveiled new technologies and new insights into important molecular mechanisms. Improved mouse cancer models, most notably 'knock-in' mice genetically engineered to be tumor-prone, may be more relevant to the human condition than traditional mouse models of cancer, oncologist David Tuveson reported.

Scientists are also developing a deeper understanding of how cells control the transitions between active, transiently inactive, and stably inactive chromatin, and testing new drugs that may help control these switches.

Working out the mechanical details of DNA repair, researchers now find that two complexes, not one, provide the specificity and sensitivity required - challenging a dogma in the field.

Reaper, a Drosophila protein that promotes apoptosis, works by destabilizing Inhibitors of apoptosis proteins and by blocking protein synthesis, researchers found. In an unexpected twist, they discovered Reaper-related proteins in several encephalitis-causing viruses, and speculate that the Reaper-like protein functions contribute to disease pathology.

The current ban on new stem-cell lines in the US represents a threat to further progress in the field, speakers cautioned. Stanford University researcher Irving Weissman lamented that the limited number of stem cell lines currently available to researchers in the US in insufficient to fulfill their promise. The existing cell lines have a limited lifespan, and using them may also create misleading results, he warned.

Perhaps inevitably, controversy reared its head at the meeting. One month after the publication of two high-profile papers linking the simian virus SV40 to human lymphomas, there was heated discussion of accusations that SV40-contaminated polio vaccine stocks are to blame for certain cancers.

But the meeting ended on a high note in one of its last sessions. The audience erupted with enthusiasm after the premiere of the first-ever film showing cancer cells metastasizing through normal tissue, at a session that featured metastasis experts including AACR award-winner Lynn Matrisian.

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