Chemical Genetic-based Cancer Therapies Bill Sullivan, Dept. of MCD Biology In order to understand the molecular and cellular events guiding the initial nuclear divisions of the Drosophila embryo, the Sullivan laboratory carries out screens for mutations that specifically disrupt syncytial divisions. These screens have yielded mutations in conserved cell cycle checkpoint genes. Their findings suggest new strategies for destroying checkpoint-compromised cancer cells and have enabled them to develop in vivo screens for anti-cancer reagents.

The cytological and timing effects of anti-cancer agents can be readily tested using the rapid ten minute Drosophila embryonic cycles.

Cancer, Genes, and a Search for Effective Chemotherapies

Effective anti-cancer therapies destroy tumor cells with minimal effect on normal cells. Most current chemotherapies, as well as X-irradiation treatment, exploit subtle physiological differences in proliferation or nutritional requirements of normal and tumor cells.

Unfortunately, most current drugs are relatively nonspecific, broadly acting agents, and kill or damage large numbers of healthy cells along with malignant ones. In the past, a common problem with many anti-cancer drugs is that they have been selected on the basis of their statistical success with cancers that originate in the same tissue. However, we now know cancers from the same tissue are genetically and physiologically quite distinct. This may explain why, for example, a drug that is effective for one form of lymphoma may be useless in treating another type.

A New Chemical Genetics Approach to Cancer Therapy

An alternative approach to developing effective chemotherapies has emerged during the past two decades from work that has identified genetic lesions associated with specific cancers. Therapies that exploit these genetic differences are likely to prove more effective at targeting tumors without harming normal cells. Some critics of this approach have suggested that such genetically based chemotherapies are impractical, because each clonally-derived tumor line results from the accumulation of a unique set of lesion. However, recent evidence has shown that specific genetic mutations are common in a wide array of cancers.

Some of the most conserved lesions occur in cell cycle checkpoints - genes that play an important role in monitoring and maintaining the integrity of the genome. For example, the mammalian p53 gene, a DNA damage checkpoint, is estimated to mutate in 50% of all human cancers. Proponents of the genetic approach are convinced that drugs can be developed that selectively destroy cells that have been disrupted in key cell cycle checkpoints. A recent study based on this concept examined the effects of anti-cancer drugs on checkpoint-compromised S. cerevisiae strains (Simon et al., 2000 Cancer Research, 60 (2): 328-33). The results show that isogenic yeast strains defective in DNA repair and checkpoint functions are, indeed, sensitive to a specific set of clinically tested anti-cancer drugs. This type of approach has led to the identification of two classes of anti-cancer agents: 1) those which function relatively independent of the genetic background and 2) those whose efficacy is greatly enhanced in cells disrupted in a specific cell cycle checkpoint. Reagents in the latter class are especially promising as drugs that could pinpoint and destroy only cancer cells.

The fruitfly Drosophila is an excellent system for examining the genetic basis of cancer. In one research project in my laboratory, we conduct screens for agents that target the specific genetic lesions that initiate the disease.

Motivated by this rationale, the Sullivan laboratory has begun to design in vivo screens to functionally and cytologically profile anti-cancer drugs and cell cycle inhibitors. They use the Drosophila fruit fly system for these investigations. There are several advantages to using this system. Like humans, Drosophila is a physiologically complicated organism with many cell and tissue types. Again, much like humans, the organism undergoes a developmentally programmed, environmentally induced, apoptotic response. Moreover, over two-thirds of all known human disease genes are conserved in Drosophila. Finally, this system allows the Sullivan laboratory to perform high-resolution cytological analysis in real-time on the effects of checkpoint mutations and inhibitors on the cell cycle - an approach that would clearly be impractical to apply to human subjects.