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Mar 15, 2012 (Vol. 32, No. 6)

Biomarker Analysis Makes Strides

  • Novel Cancer Biomarker

    Click Image To Enlarge +
    Micrographs of breast cancer lesions (A) low-risk, GP88 negative, and (B) high-risk, GP88 positive, invasive ductal carcinoma [A&G Pharmaceutical]

    “Unfortunately, more than 40% of such women are not responsive or become nonresponders to these treatments,” says Ginette Serrero, Ph.D., CEO, A&G Pharmaceutical. “There is an unmet need to identify protein-based biomarkers for anti-estrogen resistance to be run alongside tests used in the standard of care that could better predict who will and who won’t respond to treatment.”

    A&G Pharmaceutical has identified one such biomarker called GP88. “This is an autocrine growth and survival factor produced, secreted, and absolutely required by the cancer cells. A&G has performed studies demonstrating that this biomarker plays a critical role in cancer development, invasiveness, and for the survival of breast and lung cancer.

    “We have developed two diagnostic kits that measure GP88 in tumor tissue and in serum of patients. The tissue test has been validated in two independent clinical trials. These demonstrated that in ER+ breast cancer patients, an elevated GP88 was correlated with a fourfold increase in the risk of disease progression. Further, ongoing prospective clinical studies have found that serum GP88 levels are elevated in breast and lung cancer patients as compared to healthy subjects.”

    Dr. Serrero also described the company’s development of a companion therapeutic. “We have developed a neutralizing monoclonal antibody against GP88 that is undergoing preclinical development. Our studies include mouse xenograft models of tamoxifen resistance. We found that when used together, the monoclonal antibody potentiated tamoxifen response.”

    Leading investigators in the field suggest that within the next five years, oncologists and their patients will have many more therapeutic options. Perhaps as many as 25 molecularly targeted agents for cancer therapy will be available.

    Within this time frame, virtually every possible mutation will have been identified in the genomes of the most common cancers. This will allow increasingly effective monitoring of the treatments for cancer by examining robust biomarkers from samples obtained by minimally invasive means.

  • Chemokines and Cytokines as Potential Markers for Personalizing Leukemia Treatment

    “Leukemic cells don’t live in isolation; they’re interacting with their environment within the bone marrow, they’re interacting with their environment in terms of the blood that flows by them,” explains Steven Kornblau, M.D., professor at MD Anderson Cancer Center.

    Dr. Kornblau is working to understand how the cytokines and chemokines that the leukemic cells might be getting exposed to also affect protein expression. The idea that researchers in his lab might find different cytokine and chemokine expression patterns within leukemic cells led to determining ways to profile large numbers of cytokines.

    The researchers considered using ELISA kits for the chemokine and cytokine studies but realized that this approach would require a significant amount of sample, plus there was concern about the impact of batch effects on results.

    "We were looking for something where we could analyze a lot of cytokines and chemokines simultaneously that also wouldn’t require too much material,” Dr. Kornblau notes. “Around that time we saw that Bio-Rad (www.bio-rad.com) was creating large cytokine kits, where you could look at numerous chemokines and cytokines simultaneously.”

    The lab used the Bio-Plex Pro™ human cytokine 27-plex assay to study a large panel of serum samples from acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) patients (178 AML and 114 MDS samples). Because MDS is often considered to be “preleukemia,” one of the questions to be addressed was whether MDS and AML exhibit similar or unique cytokine patterns.

    “The first thing we found was that for both diseases, the pattern of expression was markedly different from the 19 normal controls that we had included,” notes Dr. Kornblau. “The second thing we found was that for 24 of the 27 cytokines, there really wasn’t a difference between their expression in MDS and their expression in AML.”

    Analysis of data generated in this study led to segregation of patient samples into eight different signatures. Identification of these signatures led to their correlation to different clinical leukemic features such as cytogenetics, outcome, and remission duration.

    “We found to our surprise that there tended to be a good, an intermediate, and an unfavorable group of signatures,” says Dr. Kornblau. “These were independent of other established clinical features like cytogenetics, age, or like having an antecedent hematological disorder. We were surprised to see that the cytokine and chemokine profiles actually were prognostic on their own.”

    The results of this research set up the idea going forward that chemokine and cytokine patterns can be used to inform different therapies and enhance the ability of clinicians to affect leukemic cell growth or eliminate the resistance of those leukemic cells to different therapies already in use, according to Dr. Kornblau.

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