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Potential Clue Associated with Aggressive Prostate Cancer Identified by Rutgers Investigators

Prostate cancer is one of the most common forms of cancer in men and the leading cause of cancer deaths in white, African-American and Hispanic men, according to the Centers for Disease Control. Current treatment of prostate cancer targets androgens, hormones which promote the growth and spread of cancer cells. However, it remains unclear why, despite treatment, some prostate cancers progress and may become fatal. Researchers at Robert Wood Johnson Medical School, part of Rutgers, The State University of New Jersey, who are studying the underlying mechanisms that cause invasive tumor growth have identified a key transcription factor, a protein which regulates the flow of information from DNA, that is over-produced in treatment-resistant prostate cancer, as well as the two protein kinases that trigger the process. This finding, published and highlighted on the cover of the July issue of Molecular Cancer Research, a journal of the American Association for Cancer Research (AACR) could be utilized to develop treatments for prostate cancer that is resistant to current therapies.

The research team, led by Joseph Fondell, PhD, associate professor of pharmacology, found that in clinically localized human prostate cancer — cancer that is confined to the prostate and pelvic area — the key transcription factor termed MED1 is overexpressed, meaning that significantly more MED1 is produced than is typical. According to Fondell, the finding potentially could be used as a biomarker in cancer screenings, indicating to oncologists that the prostate cancer has become aggressive. “As MED1 is a known co-activator of androgen receptors, the overexpression of MED1 is thought to facilitate alternative gene expression patterns that drive treatment-resistant cancer cell growth in the prostate,” Fondell said.

“Our study showed for the first time that MED1 expression is elevated in malignant cells of a statistically significant number of patients with clinical prostate cancer and that this overexpression correlates with an increase in cancer cell growth and invasiveness,” said Feng Jin, PhD, a former graduate student in Fondell’s lab and first author on the study. “In addition to accelerated tumor growth, our study showed that overexpression of MED1 may also be involved with inflammation of the prostate.”

Further study of the process using mouse models that mimic human prostate cancer, showed that two protein kinases, ERK and PI3K/AKT, were overactive and responsible for MED1 overproduction, ultimately accelerating the progression and spread of prostate cancer.

“Whereas the current treatment approach for prostate cancer is to prohibit androgen production and signaling, our findings indicate that MED1 could represent a novel target for new therapies that stop the process at the molecular level, before prostate cancer can progress to an advanced stage,” added Fondell, who also is a member of Rutgers Cancer Institute of New Jersey.

Study: ERK and AKT Signaling Drive MED1 Overexpression in Prostate Cancer in Association with Elevated Proliferation and Tumorigenicity [Molecular Cancer Research]

Source: Robert Wood Johnson Medical School

Cancer Biomarker Study Data Presented at the 2013 AACR Meeting

As we’ve done in previous years here at Biomarker Commons (AACR 2011 and AACR 2012), here’s a roundup of eight research studies on cancer biomarkers that were presented last month at the American Association for Cancer Research (AACR) Annual Meeting in Washington, DC. The theme of this year’s meeting was “Personalizing Cancer Care Through Discovery Science.”

  • Biomarker Analysis Identified Women Most Likely to Benefit From T-DM1

    According to data from a subanalysis of a phase III clinical trial that led the U.S. Food and Drug Administration to approve trastuzumab emtansine (T-DM1) in February, the amount of HER2 in tumors of women with metastatic, HER2-positive breast cancer might determine how much they benefit from the drug. The findings were presented by José Baselga, M.D., Ph.D., physician-in-chief at Memorial Sloan-Kettering Cancer Center in New York.

    Source: AACR

  • Novel Serum Biomarker Bilirubin Predicted Lung Cancer Risk in Smokers

    Researchers from MD Anderson Cancer Center in Houston, Texas, used a unique multiphase study design for the metabolomics profiling of serum samples from non-small lung cancer patients, and showed that bilirubin is a potential biomarker for lung cancer risk prediction. Men who were smokers and had low bilirubin levels had increased risk for cancer incidence and mortality.

    Source: AACR

  • Biomarkers Discovered That May Help Predict Response to Drugs Targeting KRAS-mutated NSCLC

    Massachusetts General Hospital scientists have identified biomarkers that may help predict whether patients with KRAS-mutated non-small cell lung cancer (NSCLC) will respond to concurrent treatment with an MEK inhibitor and a PI3 kinase inhibitor, a drug combination currently being investigated in ongoing clinical trials.

    Source: AACR

  • Screening Blood Samples for Cancer-driving Mutations More Comprehensive Than Analyzing Traditional Tumor Biopsy

    Using a tool called BEAMing technology, which can detect cancer-driving gene mutations in patients’ blood samples, researchers from Dana-Farber Cancer Institute and Harvard Medical School showed that were able to identify oncogenic mutations associated with distinct responses to therapies used to treat patients with gastrointestinal stromal tumors (GIST).

    Source: AACR

  • More Accurate Markers Identified for Detecting Response to Epigenetic Drugs for Myelodysplastic Syndromes

    Researchers from the University of Southern California, Los Angeles, have identified and validated two DNA methylation markers that could help physicians better determine a patient’s response to DNA methyltransferase inhibitors (DNMTi) for the treatment of myelodysplastic syndromes (MDS).

    Source: AACR

  • Cohort Study Indicates That Selenium May Be Protective Against Advanced Prostate Cancer

    According to a data presented by researchers from Maastricht University in the Netherlands, a greater level of toenail selenium is associated with a significant decrease in the risk for advanced prostate cancer.

    Source: AACR

  • Comprehensive Genomic Analysis Identified Alterations in Head and Neck Cancer That Could Lead to Targeted Therapy

    A National Institutes of Health project to catalog the genetic alterations responsible for several types of cancer, in particular those with a poor prognosis, finds that head and neck squamous cell carcinomas are genomically heterogeneous. However, those cancer with certain distinctive patterns could be amenable to specific targeted therapies.

    Source: AACR

  • Novel Drug Combination Showed Antitumor Activity in Patients With Incurable BRCA-deficient Cancers

    Researchers from Dana-Farber Cancer Institute and Harvard Medical School have identified two orally available experimental drugs — sapacitabine and seliciclib — from phase I trial data that, when given sequentially, work together to elicit antitumor effects in patients with incurable BRCA-deficient cancers.

    Source: AACR

Low Levels of Serum Bilirubin Spell Higher Lung Cancer Risk for Male Smokers

Elevated levels of bilirubin in the blood get attention in the clinic because they often indicate that something has gone wrong with the liver. Now researchers have found that male smokers with low levels of the yellow-tinged chemical are at higher risk for lung cancer and dying from the disease.

A team led by researchers at The University of Texas MD Anderson Cancer Center reported its findings in a late-breaking abstract at the AACR Annual Meeting 2013 in Washington, D.C.

“Our study indicates male smokers with low levels of bilirubin are a high-risk group that can be targeted with smoking cessation help, low-dose spiral CT screening of their lungs and other preventive measures,” said senior author Xifeng Wu, M.D., Ph.D., professor and chair of MD Anderson’s Department of Epidemiology and the Betty B. Marcus Chair in Cancer Prevention.

Lung cancer usually is diagnosed at a late stage, when tumors are inoperable and treatments largely ineffective. The overall five-year survival rate is 15 percent, but it falls to 5 percent for stage 3 lung cancer patients and 1 percent for those with stage 4 disease.

Spiral CT scans catch cancer early, biomarker could reduce false positives

The National Lung Screening Trial found that low-dose spiral computed tomography screening reduces mortality among heavy smokers by 20 percent. However, 95 percent of growths found by spiral CT are false positives, a barrier to large-scale screening.

“Validated biomarkers are urgently needed to improve risk prediction for lung cancer and to reduce false positives, shifting the balance toward more effective and efficient CT screening for cancer detection,” Wu said.

The researchers started with an objective analysis of levels of metabolites — substances produced during metabolism. Bilirubin is produced during the breakdown of old blood cells.

They analyzed 60 samples divided into three groups known as “trios” — normal controls, early stage and late stage non-small cell lung cancer patients. The top three metabolites were validated in two more groups of 50 and 123 trios.

When bilirubin emerged as the most significant metabolite, another validation study was done in a prospective cohort of 435,985 people with 208,233 men in Taiwan.

Men were divided into four groups according to their serum bilirubin levels. Lower bilirubin level was associated with significantly higher rates of both lung cancer incidence and mortality.

In the Taiwanese cohort, the incidence rate per 10,000 person-years in men was 7.02 for those in the lowest bilirubin quartile (.68 mg/dL or less), compared to 3.73 in the highest quartile of bilirubin level (1.12 mg/dL or more). The mortality rate per 10,000 person-years was 4.84 for the lowest level compared with 2.46 in the highest bilirubin quartile.

Next step: Establish a risk prediction model in heavy smokers

Bilirubin makes sense as a protective agent because of its anti-oxidant, anti-inflammatory and anti-proliferative effects. “It’s plausible that bilirubin protects against lung cancer by scavenging free radicals and carcinogens associated with smoking,” said study presenter Fanmao Zhang, a doctoral candidate in epidemiology.

Indeed, a Belgian study showed that bilirubin in the high normal range lowered cancer mortality in men. A study in the United Kingdom showed higher bilirubin levels in the normal range were associated with lower risks of chronic obstructive pulmonary disease, lung cancer and all-cause mortality. Neither of those studies stratified their analysis of bilirubin by smoking status.

“We expected that bilirubin might be protective, but our finding that bilirubin levels affect only smokers was somewhat of a surprise,” Wu said. “Our discovery that low levels increase lung cancer risk is unique.”

Smokers in the two middle cohorts of bilirubin levels also had higher lung cancer risk than those in the highest quartile. As an objective risk index for lung cancer and all-cause mortality, low levels of bilirubin should send an urgent message to quit smoking, said Chi Pang Wen, M.D., Ph.D., co-lead author from National Health Research Institutes, Taiwan.

The next step, Wu said, is to evaluate the predictive value of serum bilirubin in heavy smokers and to establish a risk prediction model that incorporates bilirubin and other biomarkers with clinical and epidemiological data to improve the efficiency of lung cancer risk prediction.

Source: EurekAlert!

Biomarker Analysis Identified Women Most Likely to Benefit From T-DM1

For women with metastatic, HER2-positive breast cancer, the amount of HER2 on their tumor might determine how much they benefit from a drug called trastuzumab emtansine (T-DM1), according to data from a subanalysis of the phase III clinical trial that led the U.S. Food and Drug Administration to approve the drug on Feb. 22, 2013. These findings were presented by José Baselga, M.D., Ph.D., physician-in-chief at Memorial Sloan-Kettering Cancer Center in New York, N.Y., at the AACR Annual Meeting 2013, held in Washington, D.C., April 6-10.

“EMILIA was a landmark phase III clinical trial,” said Baselga. “It showed that T-DM1 prolonged progression-free and overall survival for patients with HER2-positive metastatic breast cancer that had been previously treated with trastuzumab and a taxane chemotherapy compared with lapatinib plus capecitabine. Also, it provided proof-of-concept that a new class of drugs called antibody-drug conjugates can benefit patients.”

Antibody-drug conjugates consist of an antibody attached to a toxic chemotherapy, according to Baselga. In the case of T-DM1, the antibody is trastuzumab and the toxic chemotherapy is emtansine. Trastuzumab recognizes the protein HER2, which is found at high levels in HER2-positive breast cancers, and targets the emtansine to the HER2-positive cancer cells, which are killed by the toxic chemotherapy.

In this subanalysis, Baselga and colleagues analyzed tissue samples from patients enrolled in EMILIA to examine whether tumor levels of HER2, as assessed by the amount of HER2 messenger ribonucleic acid (mRNA), affected treatment response. Patients with tumor samples expressing greater than the median amount of tumor HER2 mRNA were considered to have high levels of HER2. Those with tumor samples expressing the median amount of tumor HER2 mRNA or less were considered to have low levels of HER2.

“Even though everyone enrolled in the clinical trial had breast cancer expressing elevated levels of HER2, we know that each person’s tumor has different molecular features,” said Baselga. “Even the degree to which HER2 expression is elevated differs from patient to patient.”

Consistent with the prior analysis, he and his colleagues found that all patients treated with T-DM1 had significantly longer progression-free and overall survival compared with those treated with lapatinib and capecitabine (9.6 months progression-free survival versus 6.4 months; and 30.9 months for overall survival versus 25.1 months).

Patients with tumors expressing higher levels of HER2 derived greater benefit from treatment with T-DM1 compared with patients with tumors expressing lower levels of HER2: Overall survival was 34.1 months for those with high levels of HER2 versus 26.5 months. For patients with tumors expressing higher levels of HER2, those receiving T-DM1 had a 47 percent decreased risk for death compared with those receiving lapatinib and capecitabine.

The researchers also investigated whether tumor mutations in the PIK3CA gene affected treatment response. According to Baselga, patients with PIK3CA-mutated, HER2-positive breast cancer normally do not respond as well to treatment with conventional HER2-targeted therapies such as trastuzumab compared with patients without PIK3CA mutations in their tumors.

However, for patients treated with T-DM1, PIK3CA mutation status did not significantly decrease progression-free survival.

“Our findings are an important step toward identifying the best therapy for individual patients with HER2-positive breast cancer,” said Baselga. “HER2-positive breast cancer is not a uniform disease; each patient is different. These data help us as we look to identify a panel of molecular features that we can use to make informed treatment decisions.”

Kadcyla (ado-trastuzumab emtansine or T-DM1) is a trademark of Genentech, a member of the Roche Group.

Source: American Association for Cancer Research

Molecular Response Launches TargetXTM Platform for Rapid Discovery & Validation of New Oncology Targets

Molecular Response recently announced the launch of its TargetX platform for rapid discovery and validation of new oncology targets. The program provides partners with access to the world’s largest bank of living tumor specimens, matched genomic database, and in vivo/ex vivo patient derived tumor models for validation. The integrated platform enables investigators to do in days what used to take months.

Target discovery and validation in oncology has largely relied on molecular and functional studies performed in cell lines. Recent advances in genomics have now created large databases based on well-characterized tumor tissue, which has enabled direct investigation of patient tumors for novel targets. Following these discoveries, it is routine to perform functional studies in cell line-based systems; however, it is often challenging to find a relevant cell line model and if found, there are often numerous factors which confound biology when using historical cell lines for functional studies. The result can be a process which takes considerable time and does not readily translate to clinical relevance.

“TargetX is the largest scale genomic database matched to living patient-derived tumor models,” said Dr. Mohit Trikha, CSO of Triphase Accelerator and founder of Drug Design Corp. “We plan to access it for our drug pipeline development and biomarker identification; having everything in one place allows us to do in days what used to take months. Additionally, we can now work with living patient derived tumor samples rather than cultured cell lines.”

The platform relies on Molecular Response’s proprietary bank of more than 144,000 patient derived tumor cells, of which nearly 400 tumors have been genomically characterized and databased for target discovery studies. The database is growing, but currently features the following cancer indications: colon carcinoma, NSCLC, melanoma, ovarian carcinoma, prostate cancer and Non-Hodgkins Lymphoma. Upon discovery of a novel target, tumors of interest are immediately implanted into mice to perform functional studies in direct patient derived models–either in vivo or ex vivo. Molecular Response currently has more than 60 such patient derived xenograft models established for in vivo studies.

“We continue to focus on the use of patient derived models, both in vivo and ex vivo, for advancing oncology drug development,” said Thomas Broudy, CSO of Molecular Response. “Everybody would like to perform studies in the patient derived tumor setting starting as early as possible, but without the resource to do so, it’s nearly impossible. TargetX now enables you to do that.”

Molecular Response presented results from the TargetX platform at the AACR meeting; the company has identified a novel kinase target for potential therapeutic development. They investigated prevalence of target overexpression across 7 cancer indications, and identified melanoma as a clinical indication of high interest. Growth characteristics from patient tumors featuring high kinase gene expression vs. low expression were examined to help characterize the role of this target in oncology disease progression. Functional studies in these patient derived models to further validate the novel kinase are ongoing, as is a small molecule and antibody-based therapeutic development program.

Source: Business Wire