New Drugs Aim to Defeat Tumor Resistance to EGFR Inhibitors


In recent years, many people with non-small cell lung cancer (NSCLC) have been successfully treated with drugs called EGFR inhibitors. But over time, most patients develop resistance, and the drugs stop working. Researchers are hard at work developing new drugs to help patients who can no longer be treated with EGFR inhibitors.

EGFR inhibitors get their name from a gene called EGFR. Many lung cancer tumors have mutations in this gene. These mutations convert EGFR from a normal gene into a cancer gene that initiates and promotes cancer growth. Approximately 10% to 15% of white and 30% to 35% of Asian patients with NSCLC have EGFR mutations. Continue reading…


Laboratory Studies Show Potential Benefit of Using Existing Drug to Treat Some Lung Cancers

Editor’s note: This article discusses the results of a laboratory study done in mice and human cells. The drug has not yet been tested in lung cancer patients, although it is currently being tested in patients with other types of cancer.

“An existing drug may help some patients with non-small-cell lung cancer (NSCLC) whose tumors have become resistant to chemotherapy, finds a study from Boston Children’s Hospital and the Dana-Farber Cancer Institute (DFCI). The findings, in human cancer cells and in mice, suggest a window of vulnerability in NSCLC, the leading cause of cancer-related deaths worldwide.1 The work was published online today by the journal Nature.

“NSCLC is a highly genetically complex cancer with many different subtypes, each bearing different mutations. In two common subtypes that do not respond to standard chemotherapy—tumors with BRG1 or EGFR mutations—the researchers increased the effectiveness of etoposide, a common chemotherapy agent, by adding an epigenetic therapy already in clinical testing.

“Conversely, when the same epigenetic therapy (inhibition of an enzyme known as EZH2) was added to certain tumors without BRG1 and EGFR mutations, the tumors become more resistant to chemotherapy. Together, the findings advance the idea of individualized, ‘precision medicine’ in cancer, incorporating epigenetic therapy guided by tumor genetic testing.”


Moffitt Researchers Discover Mechanism Leading to Drug Resistance, Metastasis in Melanoma Patients

The gist: New research suggests that some melanoma patients might benefit from a treatment schedule that alternates BRAF inhibitor drugs with MEK inhibitor drugs. The scientists hypothesize that this schedule could help prevent drug resistance and metastasis. The researchers set out to figure out why patients who receive BRAF inhibitors develop more metastases than patients on standard chemotherapy. They found that unusually high activity of a protein called EphA2 on cancer cells may be the culprit. Taking away BRAF inhibitors seemed to lower the aggressiveness of these cells. So, periodically taking away BRAF inhibitors from patients might theoretically help stave off resistance and metastasis.

Moffitt Cancer Center researchers have discovered a mechanism that leads to resistance to targeted therapy in melanoma patients and are investigating strategies to counteract it. Targeted biological therapy can reduce toxicity and improve outcomes for many cancer patients, when compared to the adverse effects of standard chemotherapeutic drugs.  However, patients often develop resistance to these targeted therapies, resulting in more aggressive cells that can spread to other sites or cause regrowth of primary tumors.

“B-Raf is a protein that is frequently mutated in human cancers, leading to increased tumor cell growth, survival and migration.  Drugs that target B-Raf or another protein in the same network called MEK have proved effective in clinical trials. Several B-Raf and MEK inhibitors have been approved with the combination of a B-Raf and a MEK inhibitor being the current standard of care for patients with B-Raf mutant melanoma. However over time many patients become resistant to B-Raf and B-Raf/MEK inhibitor therapy.

“Moffitt researchers found that patients who are on B-Raf inhibitor drugs develop more new metastases than patients who are on standard chemotherapy. The researchers wanted to determine how this acquired resistance develops in order to devise better treatment options for patients. They found that melanoma cells that are resistant to B-Raf inhibitors tend to be more aggressive and invasive, thereby allowing the tumor to spread to a new organ site.  They used a large screening approach and discovered that this resistance and aggressive behavior was due to high activity of a cell surface protein called EphA2, which is also found on glioblastoma stem cells.”


New Guideline Will Expand List of Lung Cancer Molecular Tests Doctors Can Use to Help Make Treatment Decisions

The gist: A new guideline will expand the list of tumor abnormalities that doctors can test for to help their lung cancer patients make treatment decisions. Different drugs have been developed to treat patients with different tumor abnormalities, such as mutations in the ALK and EGFR genes. Molecular testing lets doctors see which abnormalities a patient might have, and suggest the best-fitting treatments. The new guidelines will include recommendations for molecular testing of abnormalities in the  ROS1, MET, ERBB2, RET, NTRK1, ALK, and EGFR genes.

“The College of American Pathologists (CAP), the International Association for the Study of Lung Cancer (IASLC), and the Association for Molecular Pathology (AMP) are teaming to revise the evidence-based guideline, “Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors.”

“The updated guideline will include new recommendations for ALK testing by IHC, ALK-EGFR resistance, and a number of emerging target molecular targets which will include, but is not limited to, ROS1, MET, ERBB2, RET, NTRK1. Multiplexed “Next Generation Sequencing” multigene panels and the reassessment of immunohistochemistry will be reviewed. The role of rebiopsy and repeat analysis in the setting of post-treatment relapse, along with testing of blood samples for mutations in circulating tumor cells, cell free tumor DNA, or exosomes will be considered.

“The revision of the guideline will again be based on evidence from unbiased review of published experimental literature. The revisions will be recommended by an expert panel made up of renowned worldwide leaders in the field. The revision will start in early 2015, taking around 18 months to complete.

” ‘Although only one year has passed since the molecular testing guideline was published, rapid accumulation of scientific knowledge and new evidence in this field indicate that the guidelines should be updated. Thus, an update has begun that includes an expanded list of genes and new methods that are clinically relevant,’ said Yasushi Yatabe, MD, PhD, chief, Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Nagoya, Japan and IASLC member.”


Strategy Might Thwart Resistance to a Common Prostate Cancer Treatment

“Conventional wisdom has it that high levels of testosterone help prostate cancers grow.”However, a new, small study suggests that a treatment strategy called bipolar androgen therapy—where patients alternate between low and high levels of testosterone—might make prostate tumors more responsive to standard hormonal therapy.

“As the researchers explained, the primary treatment for advanced prostate cancer is hormonal therapy, which lowers levels of testosterone to prevent the tumor from growing. But there’s a problem: Prostate cancer cells inevitably overcome the therapy by increasing their ability to suck up any remaining testosterone in the body.

“The new strategy forces the tumor to respond again to higher testosterone levels, helping to reverse its resistance to standard therapy, the researchers say.

“If confirmed in several ongoing larger trials, ‘this could lead to a new treatment approach’ for prostate cancers that have grown resistant to hormonal therapy, said lead researcher Dr. Michael Schweizer, an assistant professor of oncology at the University of Washington School of Medicine in Seattle.”


PIK3CA Mutations Matter in HER2-Positive Breast Cancer

The gist: Recent research suggests that women whose tumors have a mutation in the PIK3CA gene may be resistant to treatment with the drugs trastuzumab (Herceptin) and lapatinib. However, two new studies say that PIK3CA mutations can’t be used to predict how well Herceptin and lapatinib will work.

“While preclinical studies indicate that PIK3CA mutations result in resistance to the two HER2-targeted therapies trastuzumab and lapatinib, two recently published studies suggest that this mutation cannot be used as a predictive biomarker to guide therapy.

“The first study found that PIK3CA mutations are associated with a decreased benefit to neoadjuvant HER2-directed therapies. The second study showed that PIK3CA mutations did not affect outcomes for HER2-positive patients receiving adjuvant trastuzumab treatment.

“Preclinical studies using HER2-positive cell lines have previously shown that an additional mutation in PIK3CA, the alpha-catalytic subunit of PI3K, results in downstream constitutive signaling, making breast tumor cells that harbor both aberrations resistant to trastuzumab and lapatinib. PIK3CA is among the most commonly mutated oncogene in breast cancer and is present in about one-fourth of all HER2-positive breast cancers. Because of this prevalence and the effect of PI3K pathway activation on HER2 therapy, clinicians have posited that PIK3CA mutations may serve as predictive biomarkers, both preventing ineffectual therapy in some patients and guiding appropriate treatment choices.”


New Cancer Vaccine Explored as Potential Treatment for Prostate Cancer Patients with Rising PSA

The gist: A new vaccine treatment  called Prostvac might help treat advanced prostate cancer patients whose tumors are resistant to hormone therapy and who have had either surgery or radiation. Prostvac boosts a patient’s own immune system to fight cancer.  A small clinical trial showed that Prostvac is safe and can be given to patients earlier. More research is needed to see just how well the vaccine works.

“Aiming to increase treatment options for prostate cancer patients who have an early relapse, investigators from a multi-institutional cooperative group — including Rutgers Cancer Institute of New Jersey — have demonstrated that a vaccine therapy that stimulates the body’s own immune defenses can be given safely and earlier in the course of prostate cancer progression.

“As part of a Phase II clinical trial, adult patients with advanced prostate cancer (as evidenced by two rising prostate-specific antigen or PSA values and no visible metastasis) whose cancer is resistant to hormone therapy and had either surgery or radiation were recruited from member institutions in the ECOG-ACRIN Cancer Research Group. In their work, published in the current online edition of European Urology, ECOG-ACRIN investigators examined two different experimental treatment options.

“In step one, patients were treated with PROSTVAC-V/TRICOM and PROSTVAC-F/TRICOM. PROSTVAC-V is derived from a vaccinia virus that was used for many years to vaccinate against smallpox. This virus is modified to produce a PSA protein that helps focus the body’s immune response to the PSA in the prostate tumor. In addition, it is modified to produce three other proteins that help increase an immune cell’s ability to destroy its target (TRICOM). PROSTVAC-F is made from the fowlpox virus, which is found in birds and not known to cause any human disease. It contains the same genetic material as PROSTAC-V, but is given multiple times to further boost the body’s immune system.”


Adding Everolimus Does Not Improve Trastuzumab/Paclitaxel Combo as Initial Treatment for HER2+, Advanced Breast Cancer

The gist: In a clinical trial, people with HER2-positive, advanced breast cancer did no better when given the three-drug combo trastuzumab + paclitaxel + everolimus as a first treatment than when given just trastuzumab + paclitaxel. A previous trial showed that everolimus + trastuzumab + vinorelbine could help patients overcome resistance to trastuzumab, but only if they had already been treated for their cancer. Researchers wondered whether adding everolimus would help prevent trastuzumab resistance.

“The addition of everolimus to weekly trastuzumab (Herceptin) plus paclitaxel did not improve outcomes in the phase III BOLERO-1/TRIO-019, but did provide a “signal” in the hormone receptor–negative subset. The study was reported at the 2014 San Antonio Breast Cancer Symposium by Sara A. Hurvitz, MD, of the University of California, Los Angeles (Abstract S6-01).

“ ‘Trastuzumab has dramatically improved outcomes for patients, however, it’s not a win for everyone. Resistance to treatment remains a clinically unmet challenge,’ she said at a press briefing. One means of counteracting resistance could be to add a drug that would inhibit the mTOR pathway in early metastatic disease, according to Dr. Hurvitz.

“In the previously reported BOLERO-3 trial, everolimus added to trastuzumab and vinorelbine did significantly improve progression-free survival for patients with trastuzumab-resistant previously treated cancer.

“ ‘We were interested in evaluating whether inhibiting mTOR early in metastatic disease will help delay the development of resistance to HER2-targeted therapy,’ she said.”


Combining Drugs May Help Fight Drug Resistance in Breast Cancer

Note: This article describes research that was done in a laboratory setting, and not in people. However, the drug combination (ganetespib plus hormone therapy) is being tested in patients in clinical trials.

“US researchers have found that combining conventional hormone therapy with an experimental cancer drug helped overcome drug resistance in breast cancer cells in the lab.

“The research focused on a molecular ‘Sherpa’ that helps cells adapt to stressful environments, known as heat-shock protein 90 (HSP90)…

“Trials of ganetespib in combination with hormone therapy are now underway in the US, and the researchers are hoping to see results within the next few years.”