103rd Annual American Association of Cancer Research (AACR) Meeting

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One way to tackle a tumor is to take aim at the metabolic reactions that fuel their growth. But a report in the February Cell Metabolism, a Cell Press Publication, shows that one metabolism-targeted cancer therapy will not fit all. That means that metabolic profiling will be essential for defining each cancer and choosing the best treatment accordingly, the researchers say.

The evidence comes from studies in mice showing that tumors' metabolic profiles vary based on the genes underlying a particular cancer and on the tissue of origin.

"Cancer research is dominated now by genomics and the hope that genetic fingerprints will allow us to guide therapy," said J. Michael Bishop of the University of California, San Francisco. "The issue is whether that is sufficient. We argue that it isn't because metabolic changes are complex and hard to predict. You may need to have the metabolome as well as the genome."

Just as a cancer genome refers to the complete set of genes, the metabolome refers to the complete set of metabolites in a given tumor.

The altered metabolism of tumors has been considered a target for anticancer therapy. For instance, tumors and cancer cell lines consume more glucose than normal cells do, a phenomenon known as the Warburg effect. There has often been the impression that such changes in metabolism are characteristic of cancers in general, but cancer is a genetically heterogeneous disease. The team led by Bishop and Mariia Yuneva wondered how metabolism might vary with the underlying genetic causes of cancer.

They found in mice that liver cancers driven by different cancer-causing genes (Myc versus Met) show differences in the metabolism of two major nutrients: glucose and glutamine. What's more, the metabolism of Myc-induced lung tumors is different from Myc-induced liver tumors.

"Our work shows that different tumors can have very different metabolisms," Yuneva said. "You can't generalize."

Bishop and Yuneva say their findings also highlight glutamine metabolism as a potential new target for therapy in some tumors, noting that the focus has been primarily on glucose metabolism. Interestingly, the data shows that a version of a glutaminase enzyme normally found in kidney cells turns up in cancerous liver cells. That means there might be a way to attack the metabolism of the cancer without damaging normal liver tissue.

"We shouldn't lose sight of the rather immediate therapeutic potential," Bishop said.

The researchers will continue to inventory metabolic variation in mouse models. Ultimately, they say it will be important to catalogue the metabolic variation in the much more complex, human setting.

References: Cell Press

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The genomic profile is so complicated, with one thing affecting another, that it isn't sufficient and not currently useful in selecting drugs. Because metabolic changes are complex and hard to predict, metabolic profiling will be essential for selecting best treatment.

In drug selection, molecular (genomic) 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 predisposition to drug response. It attempts to link surrogate gene expression to a theoretical potential for drug activity.

It relies upon a handful of gene patterns which are thought to imply a potential for drug susceptibility. In other words, molecular testing tells us whether or not the cancer cells are potentially susceptible to a mechanism/pathway of attack.

It doesn't tell you if one targeted drug (or combination of targeted drugs) is better or worse than another targeted drug (or combination) which may target a certain or a small number of mechanisms/pathways.

Functional profile testing doesn't dismiss DNA testing, it uses all the information, both genomic and functional, to design the best targeted treatment for each individual, not populations. It tests for a lot more than just a few mutations.

Functional profiling consists of a combination of a (cell morphology) morphologic endpoint and one or more (cell metabolism) metabolic endpoints. It studies cells in small clusters or micro-spheroids (micro-clusters). The combination of measuring morphologic and metabolic effects at the whole cell level.

The cell is a system, an integrated, interacting network of genes, proteins and other cellular constituents that produce functions. One needs to analyze the systems' response to targeted drug treatments, not just a few targets (pathways).

Metabolomics is a newly emerging field of "omics" research concerned with the comprehensive characterization of the small molecule metabolites in biological systems. It can provide an overview of the metabolic status and global biochemical events associated with a cellular or biological system.

An increasing focus in metabolomics research is now evident in academia, industry and government, with more than 500 papers a year being published on this subject. Indeed, metabolomics is now part of the vision of the NIH road map initiative (E. Zerhouni (2003) Science 302, 63-64&72).

Many other government bodies are also supporting metabolomics activities internationally. Studying the metabolome (along with other "omes") will highlight changes in networks and pathways and provide insights into physiological and pathological states.

The concept of Systems Biology and the prospect of integrating transcriptomics, proteomics, and metabolomics data is exciting and the integration of these fields continues to evolve at a rapid pace. Developments in informatics, flux analysis and biochemical modeling are adding new dimensions to the field of metabolomics.

To be able to walk from genetic or environmental perturbations to a phenotype to a specific biochemical event is exciting. Metabolomics has the promise to enable detection of disease states and their progression, monitor response to therapy, stratify patients based on biochemical profiles, and highlight targets for drug design.

The metabolomics field builds on a wealth of biochemical information that was established over many years.

Source:
Cell Function Analysis
The Metabolomics Society

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Dr. Robert Nagourney
Medical and Laboratory Director
Rational Therapeutics, Inc.
Long Beach, California

In many ways the era of targeted therapy began with the recognition that breast cancers expressed estrogen receptors, the original work identified the presence of estrogen receptors by radioimmunoassay. Tumors positive for ER tended to be less aggressive and appear to favor bone sites when they metastasized. Subsequently, drugs capable of blocking the effects of estrogen at the estrogen receptor were developed. Tamoxifen competes with estrogen at the level of the receptor. This drug became a mainstay with ER positive tumors and continues to be used today, decades after it was first synthesized.

Recognizing that some patients develop resistance to Tamoxifen, additional classes of drugs were developed that reduced the circulating levels of estrogen by inhibiting the enzyme aromatase, this enzyme found in adipose tissue, converts steroid precursors to estrogen. Despite the benefits of these classes of drugs known as SERMS (selective receptor modulators), many patients break through hormonal therapies and require cytotoxic chemotherapy.

With the identification of HER-2 amplification, a new subclass of breast cancers driven by a mutation in the growth factor family provided yet a new avenue of therapy – trastuzumab (Herceptin). For HER-2 positive breast cancers Herceptin has dramatically changed the landscape. Providing synergy with chemotherapy this monoclonal antibody has also been applied in the adjuvant setting offering survival advantage in those patients with the targeted mutation.

Reports from the San Antonio breast symposium held in Texas last December, provide two new findings.

The first is a clinical trial testing the efficacy of pertuzumab. This novel monoclonal antibody functions by preventing dimerization of HER-2 (The target of Herceptin) with the other members of the human epidermal growth factor family HER-1, HER-3 and HER-4. In so doing, the cross talk between receptors is abrogated and downstream signaling in squelched.

The second important finding regards the use of everolimus. This small molecule derivative of rapamycin blocks cellular signaling through the mTOR pathway. Combining everolimus with the aromatase inhibitor exemestane, improved time to progression.

While these two classes of drugs are different, the most interesting aspect of both reports reflects the downstream pathways that they target. Pertuzumab inhibits signaling at the PI3K pathway, upstream from mTOR. Everolimus blocks mTOR itself, thus both drugs are influencing cell signaling that channel through metabolic pathways PI3K is the membrane signal from insulin, while mTOR is an intermediate in the same pathway.

Thus, these are in truest sense of the word, breakthroughs in metabolomics.

Much like genomics aims to unravel the structure of the genome, metabolomics focuses on understanding the many small molecule metabolites that result from a cell’s metabolic processes.

There are an estimated 5,000 - 20,000 endogenous human metabolites, and analysing their production gives an accurate picture of the physiology of a cell at a given moment in time. Whereas the cell’s genotype can predict its physiology to a limited extent, metabolomics also takes phenotype – and therefore environmental conditions – into account, allowing a more precise measure of actual cell physiology.

For research, the study of metabolomics provides the means to measure the effects of a variety of stimuli on individual cells, tissues, and bodily fluids.

By studying how their metabolic profiles change with the introduction of chemicals or the expression of known genes, for example, researchers can more effectively study the immediate impact of disease, nutrition, pharmaceutical treatment, and genetic modifications while using a systems biology approach.