No announcement yet.

New Targets in Breast Cancer Therapy

  • Filter
  • Time
  • Show
Clear All
new posts

    New Targets in Breast Cancer Therapy

    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.
    Gregory D. Pawelski

    For Personalizing Cancer Therapy, Metabolic Profiles Are Essential

    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
    Gregory D. Pawelski


      Metabolic Profiles Are Essential For Personalizing Cancer Therapy

      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).

      Source: Cell Function Analysis
      Gregory D. Pawelski


        Georgetown Science Research Breakthrough Keeps Cancer Cells Alive in Lab

        Researchers say they may have made a science research breakthrough in the fight against cancer by discovering how to keep tumor cells alive in the lab. Up until recently, scientists haven’t been able to keep cells alive in a way where they look and act like they would in the body. Doctors previously had to freeze or set in wax biopsied tissue to make a diagnosis.

        Georgetown University’s Lombardi Comprehensive Cancer Center in Washington, D.C. was behind the discovery. Funded by grants from the National Institutes of Health, Department of Defense fellowship funding and an internal grant from Georgetown's Lombardi Cancer Center Support Grant from the National Cancer Institute, researchers have filed two patent applications for the new technology.

        Doctors hope that this advance might allow them to test numerous cancer-killing drugs on a patient’s own tumor cells in the lab before choosing a therapy that will work well. According to Richard Schlegel, who serves as chairman of the Department of Pathology at Georgetown, the ability to grow true cancer cells could change the way basic science works, too. Cancer cells often accumulate genetic changes in labs, and they no longer resemble the original tumor.

        The pioneering new method borrows from a simple method used by stem cell researchers, according to the American Journal of Pathology. The technique combines fibroblast feeder cells and Rho kinase (ROCK) inhibitor, which keep the cells alive and allow them to reproduce, respectively. Digital Journal reports that when both products were used to treat the cancer cells, they and the normal cells reverted to a “stem-like state,” according to Schlegel. This made it possible for researchers to compare both types of living cells, which wasn't an option before the science research breakthrough.

        Needless to say, this discovery could have wonderful consequences for patients being treated for cancer. The personalized lab work that will take place before treatment could mean a better chance at being cured.

        The 13th Annual BioResearch Product Faire event at Georgetown University is on July 19, 2012.

        Science Market Update

        Oncologist Robert A. Nagourney, MD, PhD, responds to news from Georgetown University about the use of cancer cell testing in a laboratory environment.

        Only registered and activated users can see links., Click Here To Register...
        Gregory D. Pawelski


          Use of Cancer Cell Testing

          What Georgetown does with "their" new breakthrough is to establish a cell line (immortalizes it). They may or may not have a better way of establishing cell lines. Problem is, cells lines don't recapitulate drug response patterns which exist in the body. For drug selection, it is better to directly remove tumor microclusters straight from the body and immediately test them, before they change.

          A cell line is a product of immortal cells that are used for biological research. Cell lines can perpetuate division indefinitely. Regular cells can only divide approximately 50 times. Cell lines are useful for experimentation in labs as they are always available to researchers as a product and do not require harvesting (acquiring of tissue from a host) every time cells are needed in the lab. They can clone cells from a cell line (HeLa cells).

          NCI had a huge lab working on microarrays to look for patterns of mRNA and protein expression which are predictive of chemotherapy response. They spent 2 years trying to find patterns which correlated using the NCI's various established ovarian cell lines. They thought they had something, but when they started to apply them to fresh tumor specimens, none of the results in the cell lines was applicable to the fresh tumors. Everything they'd worked out in the cell lines was not worth anything and they had to start over from square one.

          This may be something similar to what researchers at Johns Hopkins and Washington University at St. Louis had found out. Our body is 3D (three-dimensional), not 2D (two-dimensional) in form. They, and other researchers, have pointed to the limitations of 2D "cell-line" study and chemotherapy to more correctly reflect the human body. Traditionally, in-vitro (in lab) cell lines have been studied in 2D, which had inherent limitations in applicability to real life 3D in-vivo (in body) states. This should really help out research in looking for and developing new therapeutics. But when it comes to actually using those therapeutics, you need fresh "live" cells, not passaged cell lines.

          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. You may need to have the metabolome as well as the genome.

          There are many reasons why cancer cures remain out of reach, but several changes could be implemented immediately to increase our rate of success. One of them is the need to redouble our efforts in the study of basic metabolism and the growing field of metabolomics (the metabolome).
          Gregory D. Pawelski


            What is Metabolomics

            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.

            The Metabolomics Society

            Only registered and activated users can see links., Click Here To Register...
            Gregory D. Pawelski