Cancer Research Highlights
Protein May Regulate Hormone Sensitivity in Breast Cancer
New research indicates that a protein called TWIST plays a key role in the aggressiveness and progression of breast cancers by regulating estrogen receptor (ER) expression. This discovery may ultimately open the door to new treatments for ER-negative breast cancers, which are more aggressive and harder to treat than ER-positive breast cancers, said the researchers who led the study. The findings, from investigators at the Johns Hopkins University School of Medicine and the University Medical Center Utrecht in the Netherlands, were published online November 7 in Oncogene.
Unlike ER-positive breast cancers, which rely on estrogen to grow and can often be successfully treated with drugs that block the action of this hormone, ER-negative breast cancers do not need estrogen to grow. According to the new research, the loss of the ER in TWIST-expressing cells causes the cells to grow independently of estrogen and to resist the effects of antiestrogen therapy.
Previous research had shown that the TWIST gene is overexpressed in some high-grade breast cancers and may play a role in breast cancer development. To investigate how TWIST may function, the researchers examined ER expression levels in breast cancer cell lines with varying levels of TWIST expression. This analysis showed that levels of TWIST protein were inversely related to levels of ER mRNA and protein. The investigators then demonstrated that TWIST represses the ER gene by preventing its transcription.
Subsequent experiments showed that breast cancer cells that express high levels of TWIST were able to grow in culture and to form tumors in mice in the absence of estrogen. These TWIST-expressing cells and tumors continued to grow even in the presence of the antiestrogens tamoxifen and fulvestrant. When the researchers used a technique to reduce TWIST levels in these cells, the cells produced substantially more ER and became sensitive to estrogen and antiestrogens.
To determine whether the inverse relationship between TWIST and ER that was seen in cell lines also holds true in human breast tumors, the investigators assessed TWIST and ER expression levels in 73 primary tumors. They found a statistically significant inverse correlation between TWIST and ER mRNA levels in grade 1 and 2 (but not grade 3) tumors.
“Now that we know that TWIST plays a major role in controlling estrogen resistance in breast cancer, we can investigate the value of antiTWIST therapies,” said senior author Dr. Venu Raman in a press release. For example, the authors suggest, such therapies might be able to render ER-negative cancers ER-positive, making them dependent on estrogen for growth and responsive to antiestrogen therapies.
Epigenetic Therapy Shows Potential in Advanced Lung Cancer
Treatment with drugs that target epigenetic changes in genes—chemical modifications that influence gene expression but do not involve changes in the sequence of DNA—showed promise in a small clinical trial of patients with advanced non-small cell lung cancer (NSCLC), researchers reported last week. The phase I/II trial is believed to be the first to demonstrate successful treatment of a solid tumor with epigenetic therapy. Findings from the trial, led by researchers from the Johns Hopkins University, were published November 9 in Cancer Discovery.
In the trial, 45 patients with metastatic NSCLC whose tumors had returned after previous treatment received low doses of azacitidine (Vidaza) and entinostat, two drugs that target epigenetic changes involved in silencing gene activity. Median survival among trial participants was 6.4 months, which is similar to what was seen in the clinical trials that led the Food and Drug Administration (FDA) to approve the targeted therapy erlotinib (Tarceva) for patients with advanced NSCLC. (The FDA approved azacitidine for the treatment of myelodysplastic syndromes in 2004.)
Among the patients who completed at least one cycle of treatment with the two drugs, median survival was 8.6 months. Seven patients from the trial are still alive, including two who began treatment approximately 4 years ago. The trial, which was sponsored in part by NCI’s Cancer Therapy Evaluation Program, did not include a comparison group of patients who did not receive the investigational therapy.
The treatment approach takes advantage of the fact that, unlike genetic mutations, epigenetic changes are potentially reversible. High doses of the drugs used in earlier trials were too toxic for patients, so the researchers used low concentrations that were sufficient to reverse epigenetic changes but that had limited toxic side effects, explained the study’s senior author, Dr. Charles Rudin, during a press briefing.
The two drugs “were well tolerated,” Dr. Rudin said, and the researchers were surprised to see tumor responses in two patients, including one complete response that lasted 14 months. Another 10 patients had stable disease. But he cautioned that the results need to be confirmed in a larger study population.
Patients whose tumors responded to the therapy improved gradually over several months of treatment, which suggested that the treatment was indeed working via an epigenetic mechanism, study co-author Dr. Malcolm Brock noted. After stopping treatment with the two drugs, 19 patients went on to receive at least one round of chemotherapy, other targeted therapies, or both. In four of these patients, including the two longer-term survivors, tumors shrank substantially after the additional therapy.
The findings should encourage continued research on epigenetic cancer treatments, including tests of epigenetic drugs in combination with standard therapies and identification of subsets of patients most likely to respond, Dr. Jeffrey Engelman of Harvard Medical School said during the briefing. Dr. Engelman was not involved in the study.
A small, multi-institution trial has been launched to test the same drug combination as a post-surgical, or adjuvant, treatment in patients with stage I lung cancer, Dr. Brock said.
Treatment Uses Antibodies and Light to Target Cancer Cells
Researchers from NCI’s Center for Cancer Research (CCR) led by Dr. Hisataka Kobayashi have developed a new type of targeted anticancer treatment using photoimmunotherapy—a light-activated “nano-bomb” bound to a monoclonal antibody (mAb) that delivers the cellular disruptor to tumor cells. In experiments in cells grown in the laboratory and in mouse models, the treatment effectively killed cancer cells that had an excess of a protein targeted by the mAb on their surfaces but spared normal cells. These results were published online in Nature Medicine on November 6.
Traditional photodynamic (light-activated) anticancer therapy uses compounds called photosensitizers that, when exposed to a specific wavelength of light, become activated and trigger cell death. However, in addition to killing cancer cells, photosensitizers can also damage normal tissue. To make the therapy more selective for cancer cells, Dr. Kobayashi and his colleagues created hybrid compounds (conjugates) that consist of a photosensitizer called IR700 bound to one of two mAbs, trastuzumab or panitumumab. These mAbs bind to cell surface proteins called HER2 and HER1, respectively, both of which are overexpressed by some cancer cells.
Cancer cells incubated in a laboratory dish with the conjugates for as little as 1 hour died when exposed to the near-infrared wavelength of light that activates IR700. This rapid action shows that the conjugates only have to bind to the cell surface to kill cancer cells—they do not need to be absorbed by the cell like traditional photodynamic therapy drugs. The conjugates did not kill cells that did not overexpress either HER2 or HER1.
To test the conjugates in an animal model, the researchers established xenograft tumors that overexpressed HER2 or HER1 in mice. After small tumors had formed, the researchers injected the mice with one of the two conjugates and exposed them to near-infrared light 1 day later. Mice that received the treatment had their tumors shrink significantly and lived longer than untreated control mice. The researchers did not observe any toxic effects in normal tissue after 4 weeks of twice-weekly administration of the conjugates.
The fluorescence from the new conjugates may also be useful in noninvasively diagnosing tumors and monitoring response to treatment, explained the authors. “Although more testing will be needed,” said Dr. Kobayashi in a press release, “we believe this [photoimmunotherapy] method has the potential to replace some surgical, radiation, and chemotherapy treatments.”
Genetic Mutation that Raises Melanoma Risk Identified
An international group of researchers recently identified a rare genetic mutation associated with an increased risk of melanoma. The mutation, a change in the MITF gene that alters one amino acid in the MITF protein, raises melanoma risk in people with a strong family history of melanoma and also in the general population, the researchers found. The study was published online November 13 in Nature.
Mutations in two genes, CDKN2A and CDK4, are known to increase the risk of familial melanoma, with CDKN2A mutations accounting for nearly 40 percent of familial melanoma cases and CDK4 linked to melanoma risk in a small group of families in which melanoma is common.
In an effort to identify additional genes associated with familial melanoma, lead investigators Dr. Kevin Brown of NCI’s Division of Cancer Epidemiology and Genetics, Dr. Nicholas Hayward of the Queensland Institute of Medical Research, and Dr. Jeffrey Trent of the Translational Genomics Research Institute sequenced the whole genome of several individuals with melanoma from families with multiple cases of the disease. None of the family members had an alteration in the CDKN2A or CDK4 genes.
In one individual, they found a variant in MITF. This gene is involved in numerous important functions in skin cells called melanocytes, the cell type from which melanomas arise. Previous studies have shown that MITF is amplified or mutated in some melanoma tumor samples and overexpressed in others, but none of the studies implicated the gene in risk of developing the disease.
Additional studies of the same individual’s family found the MITF gene variant, called E318K, in several family members who had developed melanoma, though not all. The authors then looked for the MITF variant in samples from two large case-control studies of melanoma involving the general population, as opposed to melanoma-prone families, and found that the E318K variant was carried more frequently by melanoma case subjects than by control subjects. The gene variant was found more often in families with a stronger history of melanoma, multiple primary melanomas, or both, Dr. Brown and his colleagues reported.
The mechanism by which the MITF variant may promote melanoma development is not yet clear, explained Dr. Brown, the study’s senior author. In studies involving cell lines, however, the researchers showed that the variant altered the expression of some of the genes known to be regulated by MITF.
The findings do not change recommendations for regular screenings and other protective behaviors in individuals with a family history of melanoma, Dr. Brown added.