Lapatinib May Fight TNBC

Lapatinib, which has been approved for use on Her2-positive tumors,  is also effective against triple-negative breast cancer in lab tests on mice, according to research published in Breast Cancer Research November 12, 2013.  Lapatinib  targets EGFR and  and  p65, which are present in both HER2-positive and triple-negative breast cancer cells.  Specifically, it is effective against the NF-κB pathway that scientists believe may be a key regulator of TNBC.  Researchers suggest it should be used in combination with a proteasome inhibitor.  The study also demonstrated that lapatinib worked better than gefitinib and erlotinib, which are  specific EGFR inhibitors. 
  
In previous research, lapatinib, in combination with Herceptin, was effective against TNBC.

• Read more about TNBC in my book, Surviving Triple-Negative Breast Cancer.

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Biological pathway offers less-toxic treatment potential for some cases of TNBC

The OGF-OGFr axis, a novel biological pathway, can be modulated in human triple-negative breast cancer cells to inhibit proliferation, according to research in the June 2013 issue of Experimental Biology and Medicine. 

Exposure of human breast cancer cell lines to OGF in lab tests repressed growth within 24 hours. (That's fast, folks.) Treatment with low dosages of the opioid antagonist naltrexone (LDN) boosted OGF with minimal or no side effects, with potentially stronger effects than paclitaxel.

"What is exciting about our findings," said Ian S. Zagon, M.D., senior author and Distinguished University Professor at the University of Pennsylvania, "is that women with triple-negative breast cancer have few options because their tumors lack the necessary hormonal receptors. [Pat's note:  I would say "different options" rather than "fewer."]

Data from these studies open new doors for treatment of this population of women." Moreover, the OGF-OGFr axis is present in all types of breast cancer cells suggesting that this pathway provides additional avenues for treatment of this commonly diagnosed cancer.

Existing drugs kill TNBC drugs by targeting their own waste

Triple-negative breast cancers may be vulnerable to drugs that attack the proteasome, a cellular structure that acts as the cell's waste disposal, breaking down damaged or unneeded proteins, according to a new paper in Cancer Cell.

In lab tests, researchers selectively "turned off" genes throughout the genomes of triple-negative tumor cells. When turned off, the cells die.

These data suggest that triple-negative breast cancers may respond to treatment with drugs similar to bortezomib (Velcade), which is used in multiple myeloma.

• Read more about TNBC in my book, Surviving Triple-Negative Breast Cancer.

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Enzyme UBASH3B Linked to TNBC Progression and Growth

Scientists at  the Genome Institute of Singapore (GIS) have identified genes that are potential targets for therapeutic drugs against triple-negative breast cancer. These findings were reported in the July 2013 issue of PNAS.

In the research, they discovered that an enzyme, UBASH3B, was overexpressed in one third of TNBC patients. Deleting this gene expression inhibits TNBC growth and lung metastasis in a mouse model. They also showed that TNBC patients with high levels of UBASH3B tend to be more likely to have early recurrence and metastasis.

Lead author Dr Qiang Yu said, “It is heartening to know that UBASH3B is an important element of the pro-invasive gene network and targeting UBASH3B not only inhibits TNBC invasive growth, but also significantly reduces metastasis.”

Tan Tock Seng Hospital consultant surgeon Dr Tan Ern Yu, a collaborator and co-author of the study said, “Some TNBC patients relapse soon after standard treatment while others remain free of disease for a long time. Being able to predict which patients are more likely to relapse is important since these patients may benefit from more aggressive treatments. But currently, doctors are unable to reliably do so. Further validation will show whether UBASH3B can be developed into a means of identifying these high-risk patients as well as a new form of treatment.”

Dr Dave Hoon, Director, Department Molecular Oncology at the John Wayne Cancer Institute, USA, and co-author said, “Recent large-scale genomic analysis of breast cancer show that triple negative breast cancer are highly heterogeneous and patients tumors can have different molecular profiles.  The finding can help us develop new approaches for targeted therapy for this highly aggressive breast cancer.”

The original news release is here.

• Read more about TNBC in my book, Surviving Triple-Negative Breast Cancer.

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Androgen Drug to Be Tested for TNBC in Phase II Trial

A News Release from Medivation

Medivation, Inc.and Astellas Pharma Inc. today announced enrollment of the first patient in a global Phase 2 clinical trial evaluating enzalutamide as a single agent for the treatment of advanced, androgen receptor (AR)-positive, triple-negative breast cancer (TNBC). Medivation is conducting this study under its agreement with Astellas.

"The initiation of this Phase 2 study marks an important milestone as we expand our enzalutamide development program beyond prostate cancer to explore the clinical efficacy of enzalutamide in triple-negative breast cancer, where there is a significant unmet medical need," said David Hung, M.D., president and chief executive officer of Medivation, Inc. "We plan to present the results from the Phase 1 study in breast cancer at an upcoming scientific conference."

The Phase 2 open label, single-arm, multicenter trial plans to enroll approximately 80 patients with AR-positive, TNBC at sites in the United States, Canada and Europe. The primary endpoint of the trial is clinical benefit rate, defined as the proportion of patients with a best response of complete response, partial response or stable disease at ≥ 16 weeks. All patients will receive enzalutamide at a dose of 160 mg to be taken orally once daily. Information about patient eligibility and enrollment can be obtained by calling 800-888-7704 ext. 5473 or e-mailing clintrials.info@us.astellas.com.

TNBC is a type of cancer which does not express any of the three most commonly targeted receptors in breast cancer: estrogen, progesterone and HER2. TNBC remains an area of significant unmet medical need. Currently, there are no approved targeted therapies for these patients, who are typically treated with multiple regimens of chemotherapy. AR-positive breast cancer is a recently-identified subtype of TNBC that can express high levels of the androgen receptor.

Enzalutamide is an androgen receptor inhibitor that acts on different steps in the androgen receptor signaling pathway. Enzalutamide has been shown to competitively inhibit androgen binding to androgen receptors, and inhibit androgen receptor nuclear translocation and interaction with DNA.

NOTE: XTANDI(R) (enzalutamide) capsules is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have previously received docetaxel. It can cause fetal harm and is contraindicated in women who are or may become pregnant.

HMGA1 Turns TNBC Cells Back to More Normal and Slows Their Growth

From a News Release from the Johns Hopkins University School of Medicine

Researchers at Johns Hopkins have identified a gene that, when repressed in tumor cells, puts a halt to cell growth and a range of processes needed for tumors to enlarge and spread to distant sites. The researchers hope that this so-called “master regulator” gene may be the key to developing a new treatment for tumors resistant to current drugs.

“This master regulator is normally turned off in adult cells, but it is very active during embryonic development and in all highly aggressive tumors studied to date,” says Linda Resar, M.D., an associate professor of medicine, oncology and pediatrics, and affiliate in the Institute for Cell Engineering at the Johns Hopkins University School of Medicine. “Our work shows for the first time that switching this gene off in aggressive cancer cells dramatically changes their appearance and behavior.” A description of the experiments appears in the May 2 issue of the journal PLOS ONE.

Resar has been investigating genes in the master regulator’s family, known as high mobility groupor HMG genes, for two decades. In addition to their role in cancer, these genes are essential for giving stem cells their special powers, and that’s no coincidence, she says. “Many investigators consider cancer cells to be the evil twin of stem cells, because like stem cells, cancer cells must acquire special properties to enable the tumor to grow and metastasize or spread to different sites,” she explains.

In a previous study, she and her team devised techniques to block the HMGA1 gene in stem cells in order to study its role in those cells. In their prior work, they discovered that HMGA1 is essential for reprogramming adult cells, like blood or skin cells, into stem cells that share most, if not all, properties of embryonic stem cells.

In the newly reported study, the Resar team applied the same techniques to several strains of human breast cancer cells in the laboratory, including the so-called triple negative cells — those that lack hormone receptors or HER2 gene amplification. The Resar team blocked HMGA1 expression in breast cancer cells and followed their appearance and growth patterns.

"Remarkably, within a few days of blocking HMGA1 expression, they appeared rounder and much more like normal breast cells growing in culture,” says Resar. The team also found that the cells with suppressed HMGA1 grow very slowly and fail to migrate or invade new territory like their HMGA1-expressing cousins.

The team next implanted tumor cells into mice to see how the cells would behave. The tumors withHMGA1 grew and spread to other areas, such as the lungs, while those with blocked HMGA1 did not grow well in the breast tissue or spread to distant sites.

“From previous work, we know that HMGA1 turns on many different genes needed during very early development, but it’s normally turned off by the time we’re born,” says postdoctoral fellow Sandeep Shah, Ph.D., who led the study. “Flipping that master regulator back on seems to be necessary for a cancer to become highly aggressive, and now we’ve seen that flipping HMGA1 off again can reverse that aggressive behavior.”

The next step, Resar says, is to try to develop a therapy based on that principle. The team is working with other researchers at Johns Hopkins to see whether HMGA1-blocking molecules could be delivered to tumors inside nanoparticles. Another possible approach, she says, would be to block not HMGA1 itself, but one of the pathways or processes that it affects.

• Read more about TNBC in my book, Surviving Triple-Negative Breast Cancer.

• Please consider a donation to Positives About Negative to keep this site going.  This work is entirely supported by readers.  Just click on the Donate button in the right of the page.  Thank you!