Researchers find roadmap to next-generation cancer therapies

May 25, 2008

Pinpointing new targets for cancer treatments is as difficult as finding a needle in a haystack, yet a University of Rochester team has discovered an entire novel class of genes they believe will lead to a greater understanding of cancer cell function and the next generation of effective and less harmful therapies for patients.

In a paper in the journal Nature, available online May 25, the researchers describe how multiple cancer genes cooperate to cause malignant cell transformation. Further, they describe the discovery of approximately 100 genes that work downstream of known cancer-causing mutations, providing a host of new opportunities for intervention.

“We believe that we have found a cornerstone for development of new treatments that ultimately will allow selection of drugs and drug combinations from a pool of compounds directed against these new genes,” said lead author Hartmut Land, Ph.D., professor and chair of the Department of Biomedical Genetics at the University of Rochester Medical Center and scientific director of the James P. Wilmot Cancer Center at the URMC.

“However, much more work needs to be done to explore how our findings may lead to successful targeting of various cancer types and cancer stem cells,” he said.

Targeted cancer therapy – such as the drug Gleevec that works for patients with certain types of leukemia and gastrointestinal tumors – is based on a keen understanding of the architecture of cancer. Much has been learned in the past several years, but what has been lacking is a clear roadmap leading to dozens of new molecular targets.

Twenty-five years ago Land was among the first scientists to discover that malignant cell transformation required multiple mutations in distinct cancer genes. Ever since, he has been studying the cooperative nature of this process and the inner workings of cancer cell function.

His research group began testing, at the genomic scale, a prediction that genes responding synergistically to cooperating oncogenic mutations might act as the “drivers” toward malignancy, Land said. It now appears that this hunch has paid off.

Spear-headed by co-authors Helene R. McMurray, Ph.D., a post-doctoral fellow, and graduate students Erik R. Sampson, George Compitello and Conan Kinsey, the team found that among 30,000 cellular genes, only about 100 genes responded synergistically to the combination of two of the most prevalent cancer genes, Ras and p53, and were expressed differently in normal and cancer cells.

Accordingly, the research group termed these 100 genes CRGs, for “cooperation response genes.” By studying a subset of the CRGs, researchers also found that 14 of 24 CRGs were essential to tumor formation. In contrast, only one of 14 genes responding in a non-synergistic manner (non-CRGs) had a similar effect.

The significance of Ras and p53, and by association the CRGs, is enormous. Ras and p53 are implicated in about half of all cancers. When p53, a tumor-suppressor gene, loses its function, and when Ras becomes hyperactive, both genes play major roles in promoting uncontrolled growth of colon, pancreas and lung cancers.

Ras activation and p53 loss-of-function cooperatively work together through the CRGs, which encode proteins that regulate cell signaling, cell metabolism, self-renewal, cell differentiation and cell death.

“Indeed, CRGs may provide us with a surprisingly large and valuable set of targets for interventions that will destroy cancer cells and leave normal cells unharmed,” Land said. “We are very excited with the results.”

Source: University of Rochester

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gdpawel
4 / 5 (1) May 27, 2008
And what do you do when there are too many receptors and the cancer cell still continues to grow and divide?

When considering a 'targeted' cancer drug which is believed to act only upon cancer cells that have a specific genetic defect, it is useful to know if a patient's cancer cells do or do not have precisely that defect. Although presence of a 'targeted' defect does not necessarily mean that a drug will be effective, absence of the targeted defect may rule out use of the drug.

Cancer cells have many mutations in many different pathways, so even if one route or two is shut down by a targeted treatment, the cancer cell may be able to use other routes. Targeted drugs have not been accompanied by reliable, specific predictive tests allowing for rational and economical use of these drugs. Molecular diagnostics approved often have been mostly or totally ineffective at identifying clinical responders to the various therapies.

Gene-based testing examines a single process within the cell or a relatively small number of processes. The aim is to tell if there is a theoretical predispostion to drug response.

Gene-based testing involves the use of dead, formaldehyde preserved cells that are never exposed to 'targeted' drugs. Gene-based tests cannot tells us anything about uptake of a certain drug into the cell or if the drug will be excluded before it can act or what changes will take place within the cell if the drug successfully enters the cell.

Gene-based tests cannot discriminate among the activities of different drugs within the same class. Instead, it assumes that all drugs within a class will produce precisely the same effect, even though from clinical experience, this is not the case. Nor can Gene-based tests tell us anything about drug combinations.

If you find one or more implicated genes in a patient%u2019s tumor cells, how do you know if they are functional (is the encoded protein actually produced?). If the protein is produced, is it functional? If the protein is functional, how is it interacting with other functional proteins in the cell? Are you sure that you%u2019ve identified every single protein that might influence sensitivity or resistance to these drugs?
NBN
4 / 5 (1) May 27, 2008
gdpawel,
the authors neither claim that ALL possible anti-cancer drug targets were identified nor did they say that each of the identified CRGs will be a suitable target.

Concerning the molecular environment: Of course, it is necessary to look out for physical and functional interaction partners of the identified genes. This publications is very helpful by giving a hint in which cellular context you can find the targets. Even the information that the CRGs are involved in oncogene cooperation narrows down a lot the amount of probable interation partners!

Drug screening: On the second level of a cancer drug screen (after random available compounds were screened) some compounds showing a biological effect are chosen for further structural refinements in order to maximize the desired effect, minimize side effects, improve bioavailability... The underlying study suggests that already existing inhibitors of oncogene cooperation genes are used as lead structures and not as ultimate anti-cancer drugs. This is indeed a good point to start from and is not contradictory to combined drug testing.

Finally, which pharmacologist cares about protein interactions? Protein interations are molecular details of a whole biological context. Therefore the knowledge about protein interactions is not sufficient for drug design. However, the assays used in this study are forward in that they do not rely on molecular interactions (often misleading) but on a biological output, namly oncogene cooperation.

It is a good proposal to consider the list of new genes in the design of drug screens. Anyway, the most important molecular interactions will be elucidated soon... it´s a good Nature publication in an extremely competitive field. ;)
gdpawel
4 / 5 (1) May 29, 2008
I understand the interconnectivity of disease pathways and the rational design of optimal treatment or new strategies for treating disease.

Targeted drugs are specifically designed to block one or more critical pathways involved in cancer-cell growth and metastases. The development of these therapies stems from advances in molecular biology that have permitted the identification of qualitative and quantitative differences in gene expression between cancer cells and normal cells.

However, it doesn't matter though if there is a target molecule in the cell that the targeted drug is going after. If the drug either won't "get in" in the first place or if it gets pumped out/extruded or if it gets immediately metabolized inside the cell, drug resistance is multifactorial. What is needed is to show this at the cell "population" level, measurng the interaction of the entire genome.

The cell is a system, an integrated, interacting network of genes, proteins and other cellular constituents that produce functions. You need to analyze the systems' response to drug treatments, not just one or a few targets. There are many pathways/mechanisms to altered cellular function. Functional profiling measures what happens at the end, rather than the status of the individual pathways/mechanisms.