Science Current Events | Science News | Brightsurf.com
 

Gene therapy kills breast cancer stem cells, boosts chemotherapy

September 13, 2011
Targeted agent avoids healthy cells, blocks proteins that prevent cell death in tumors

HOUSTON -- Gene therapy delivered directly to a particularly stubborn type of breast cancer cell causes the cells to self-destruct, lowers chance of recurrence and helps increase the effectiveness of some types of chemotherapy, researchers at The University of Texas MD Anderson Cancer Center reported in the Sept. 13 edition of Cancer Cell.

In cellular and mouse studies, scientists found the gene mutation BikDD significantly reduced treatment-resistant breast-cancer initiating cells (BCICs), also known as breast cancer stem cells, by blocking the activity of three proteins in the Bcl-2 family. This genetic approach increased the benefits of lapatinib, one of the most common chemotherapy drugs for breast cancer.

"There are no effective methods to target BCICs, and they're urgently needed, especially for relapsed breast cancer patients," said senior author Mien-Chie Hung, Ph.D., vice president for basic research, professor and chair of MD Anderson's Department of Molecular and Cellular Oncology. "This research suggests a potential therapeutic approach to breast cancer stem cells that will minimize recurrence and drug resistance."

Special delivery system targets cells

Gene therapy was deposited directly into breast cancer cells with an innovative delivery system called VISA, short for versatile expression vector, which was developed at MD Anderson. It includes a targeting agent, also called a promoter, two components that boost gene expression in the target tissue and a payload -- a Bik mutant gene called BikDD known to kill cancer cells. It's all packaged in a fatty ball called a liposome and delivered intravenously.

This system has been successfully applied in pancreatic, lung, liver and ovarian cancer preclinical models. MD Anderson clinical researchers are preparing a phase I clinical trial for pancreatic cancer.

Stem cells frequently stymie treatment

Breast cancer stem cells, often resistant to chemotherapy and radiotherapy, are a major obstacle for breast cancer treatment, Hung said. If any of these cells remain after treatment, a new tumor often forms. Although lapatinib, known commercially as Tykerb®, can stabilize the level of these cells, no drugs are available to reduce them.

The Bcl-2 family of proteins - especially the subtypes Bcl-2, Bcl-xL and Mcl-1 -- is essential for breast cancer tumor growth and treatment resistance. If too many of these three proteins are present, they can cause poor prognosis and resistance to chemotherapy drugs including lapatinib, as well as paclitaxel, doxorubicin and cisplatin.

This study shows that Bcl-2 proteins help breast cancer stem cells survive, causing resistance to treatment and likelihood of recurrence. However, using VISA to deliver BikDD can block the three key Bcl-2 proteins, eliminating the stem cells.

VISA-claudin4-BikDD cuts tumor burden

The researchers engineered a VISA that contained claudin4, a protein over-expressed in breast cancer, as a targeting agent to preferentially express BikDD in breast cancer cells. This process silenced the three Bcl-2 proteins and caused the cancer cells to self-destruct. Since the VISA focused the BikDD on cancer cells, normal cells were not affected.

Treating mice with the VISA-claudin4-BikDD therapy reduced tumor volume by 75 percent compared to control mice.

They also compared VISA-claudin4-BikDD therapy to BikDD packaged with a non-specific strong promoter from cytomegalovirus. Both versions reduced tumor burden and extended survival of mice, but tumor volume in mice treated with VISA-claudin4-BikDD was half that of the CMV-BikDD-treated mice. In a safety study using an unusually high dose, 60 percent of mice treated with CMV-BikDD survived after three days; all mice treated with VISA-Claudin4-BikDD survived for the duration of the 14-day safety profile study.

In cell line experiments, the CMV-BikDD also invaded and destroyed normal cells, while the VISA-Claudin4-BikDD did not.

Agent energizes lapatinib, other drugs

BikDD made HER2-positive breast cancer cells more sensitive to lapatinib when all three Bcl-2 proteins were inhibited but not when they were inhibited separately. HER2-positive breast cancer is a particularly aggressive type that makes too much human epidermal growth factor 2; it accounts for about 20 percent of breast cancers. BikDD also sensitized EGFR+ (epidermal growth factor positive) breast cancer cells to lapatinib and several other breast cancer cells lines to paclitaxel.

Moving discovery forward

Hung said this approach is promising for breast cancer treatment, especially recurrent disease.

"VISA-claudin4-BikDD gene therapy may provide an effective strategy to inhibit breast tumor growth," he said. "It demonstrates virtually no toxicity in normal cells and produces a profound killing effect in multiple breast cancer cell lines and synergy with other agents."

Hung said the next step is to move VISA-claudin4-BikDD into a Phase I clinical trial to test its effect on patients with breast cancer.

###

This work was supported by grants from the National Cancer Institute, including MD Anderson's Specialized Program in Research Excellence grant, the MD Anderson/China Medical University Hospital Sister Institution Fund, the Breast Cancer Research Foundation, National Breast Cancer Foundation, Inc., Patel Memorial Breast Cancer Research Fund, MD Anderson's Center for Biological Pathways and NCI Cancer Center Support Grant, and the Taiwan Department of Health Cancer Center Research of Excellence Grant.

In addition to Hung, MD Anderson researchers include first author Jing-Yu Lang, Ph.D., first author, Jennifer Hsu, Ph.D., Chun-Ju Chang, Ph.D., Qingfei Wang, Ph.D., Xiaoming Xie, Ph.D., Yi Bao, Ph.D., Hirohito Yamaguchi, Ph.D. and Dihua Yu, M.D., Ph.D., Department of Molecular and Cellular Oncology; Funda Meric-Bernstam, M.D., Department of Surgical Oncology; Wendy Woodward, M.D., Ph.D., Department of Radiation Oncology; and Gabriel Hortobagyi, M.D., Department of Breast Medical Oncology.

Hung and Hsu hold joint appointments at China Medical University and Asia University, Taichung, Taiwan. Xie holds an appointment at Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China.

About MD Anderson

The University of Texas MD Anderson Cancer Center in Houston ranks as one of the world's most respected centers focused on cancer patient care, research, education and prevention. MD Anderson is one of only 40 comprehensive cancer centers designated by the National Cancer Institute. For eight of the past 10 years, including 2011, MD Anderson has ranked No. 1 in cancer care in "America's Best Hospitals," a survey published annually in U.S. News & World Report.

University of Texas M. D. Anderson Cancer Center


Related Breast Cancer Current Events and Breast Cancer News Articles


False-Positive Mammogram Anxiety has Limited Impact on Women's Well-Being
Dartmouth researchers have found that the anxiety experienced with a false-positive mammogram is temporary and does not negatively impact a woman's overall well-being.

Dual role: Key cell division proteins also power up mitochondria
An international team led by researchers at UC Davis has shown that the cyclin B1/Cdk1 protein complex, which plays a key role in cell division, also boosts the mitochondrial activity to power that process.

Cancer drugs block dementia-linked brain inflammation, UCI study finds
A class of drugs developed to treat immune-related conditions and cancer - including one currently in clinical trials for glioblastoma and other tumors - eliminates neural inflammation associated with dementia-linked diseases and brain injuries, according to UC Irvine researchers.

Low vitamin D may not be a culprit in menopause symptoms
A new study from the Women's Health Initiative (WHI) shows no significant connection between vitamin D levels and menopause symptoms. The study was published online today in Menopause, the journal of The North American Menopause Society.

Body Mass Index associated with breast cancer, regardless of body shape
A study of predominantly white women finds a larger waist circumference is associated with higher risk of postmenopausal breast cancer, but not beyond its contribution to BMI.

Blood test spots recurrent breast cancers and monitors response to treatment
Johns Hopkins Kimmel Cancer Center investigators report they have designed a blood test that accurately detects the presence of advanced breast cancer and also holds promise for precisely monitoring response to cancer treatment.

Tumor-suppressor connects with histone protein to hinder gene expression
A tumor-suppressing protein acts as a dimmer switch to dial down gene expression.

Women with diabetes less likely to have a mammogram: Study
Women with diabetes are 14 per cent less likely to be screened for breast cancer compared to women without diabetes, according to a study by researchers at the Institute for Clinical Evaluative Sciences (ICES) and Women's College Hospital.

Virus-fighting genes linked to mutations in cancer
Researchers have found a major piece of genetic evidence that confirms the role of a group of virus-fighting genes in cancer development.

Identified epigenetic factors associated with an increased risk of developing cancer
In 10% of human tumors there is a family history of hereditary disease associated with mutations in identified genes.
More Breast Cancer Current Events and Breast Cancer News Articles

The Breast Cancer Survival Manual, Fifth Edition: A Step-by-Step Guide for Women with Newly Diagnosed Breast Cancer

The Breast Cancer Survival Manual, Fifth Edition: A Step-by-Step Guide for Women with Newly Diagnosed Breast Cancer
by John Link (Author)


The updated edition of the essential resource for the 250,000 women diagnosed with breast cancer each yearBreast cancer is the leading cause of death in women from thirty-five to fifty-four years of age, and few things are as terrifying and confusing as a diagnosis of this disease. The fifth edition of The Breast Cancer Survival Manual is a concise, information-packed guide that is newly revised to contain all of the latest findings to help the woman facing treatment feel informed and empowered. John Link, M.D., a pioneer developer of Breastlink Medical Group in Southern California includes the most current medical advice on     • Tamoxifen, Herceptin, and other chemotherapy options      • The growing importance of HER2 oncogene testing      • Clinical research trials...

Fight Now: Eat & Live Proactively Against Breast Cancer

Fight Now: Eat & Live Proactively Against Breast Cancer
by Aaron Tabor, MD


Dr. Tabor’s FIGHT NOW book provides information on lifestyle choices that might improve breast health and overall health. The purpose of Dr. Tabor’s medical research is to empower you to become proactive against breast cancer now with specific food and lifestyle choices. We can make specific food and lifestyle choices to lower the risk of getting breast cancer, risk of recurrence, and risk of dying from breast cancer. The only alternative is to be reactive after you get breast cancer or have a recurrence of breast cancer. The choice is clear

Whether you are currently fighting breast cancer; are a survivor; or, simply trying to lower your risk, Dr. Tabor’s FIGHT NOW book will give you concise, critical information that you can start using today. You don’t have to read...

The Mayo Clinic Breast Cancer Book

The Mayo Clinic Breast Cancer Book
by By the breast-health experts at Mayo Clinic Cancer Center (Author)


    
     From the breast health experts at Mayo Clinic comes a guide to the many aspects of breast cancer—from prevention, to care and coping, to survival, to living with hope. Trustworthy information offered in a spirit of companionship.

     
     The Mayo Clinic Breast Cancer Book is the trusted resource for anyone wanting reliable information about this dreaded disease. Mayo Clinic set out to provide comprehensive and up-to-date facts in easy-to-understand language. They've succeeded in this handbook for those who've been diagnosed, or for those who want to give sensitive and helpful support to someone with breast cancer. The Mayo Clinic Breast Cancer Book stands out for its tone of companionship, as well as for the many patient stories that appear...

Let Me Get This Off My Chest: A Breast Cancer Survivor Over-Shares

Let Me Get This Off My Chest: A Breast Cancer Survivor Over-Shares
by Margaret Lesh (Author)


Tamoxifen hot flashes, mastectomy, reconstruction, breast cancer etiquette, Frankenboobs, bras with special attachments—Margaret Lesh shares all in her funny, heartfelt collection of essays, anecdotes, and life lessons from the perspective of a two-time breast cancer survivor. She’ll tell you when it’s okay to play the cancer card, what you should take to the hospital, and gives suggestions on how to cope in those dark moments of the soul. With practical tips sprinkled throughout, LET ME GET THIS OFF MY CHEST explores how breast cancer changed her outlook on life, offering honest insights, humor, and sensitivity as she looks for the silver lining in a not-so-great situation. Whether you are a woman diagnosed with breast cancer or whether you know someone with breast cancer, this...

The Whole-Food Guide for Breast Cancer Survivors: A Nutritional Approach to Preventing Recurrence (The New Harbinger Whole-Body Healing Series)

The Whole-Food Guide for Breast Cancer Survivors: A Nutritional Approach to Preventing Recurrence (The New Harbinger Whole-Body Healing Series)
by Edward Bauman MEd PhD (Author), Helayne Waldman MS EdD (Author), Donald I. Abrams MD (Foreword)


If you’re a breast cancer survivor, chances are you have renewed your commitment to maintaining your good health and taking care of your body. As one of the best preventative measures known to doctors and nutritionists today, a robust, cancer-fighting diet is vital to your personal plan for breast cancer prevention.The Whole-Food Guide for Breast Cancer Survivors is an essential guide for every woman seeking to understand the effect of nutritional deficiencies and environmental factors on her overall health and wellness. Based on Edward Bauman’s groundbreaking Eating for Health model, this highly comprehensive, practical approach can help you reduce the chance of breast cancer recurrence; rebuild your immune system; and enjoy a stronger, healthier body.Reduce the chance of breast...

Breast Cancer (2014): 150 Latest & Illustrated Questions & Answers

Breast Cancer (2014): 150 Latest & Illustrated Questions & Answers


Why this book -- what is so exciting in the field of breast cancer? Take a look:

* Many early breast cancers, with timely and appropriate treatments, are now curable.
* The five-year survival rate of cancers confined to the milk ducts and milk lobules (DCIS & LCIS) has gone up to 100%
* The five-year survival of Stage 1 (larger tumor or lymph node-positive tumor) has gone up to almost 90%.
* During the past 60 years, regardless of how advanced the breast cancer is, the average number of women who survive for 10 years has increased by 300%. And about 90% of women diagnosed with breast cancer will survive at least 10 years.
* Even the survival of women with breast cancer far gone to distant organs increased to almost 700 percent. Three cheers for breast...

A Breast Cancer Alphabet

A Breast Cancer Alphabet
by Madhulika Sikka (Author)


A definitive and approachable guide to life during, and after, breast cancer
 
The biggest risk factor for breast cancer is simply being a woman.  Madhulika Sikka's A Breast Cancer Alphabet offers a new way to live with and plan past the hardest diagnosis that most women will ever receive: a personal, practical, and deeply informative look at the road from diagnosis to treatment and beyond.

What Madhulika Sikka didn't foresee when initially diagnosed, and what this book brings to life so vividly, are the unexpected and minute challenges that make navigating the world of breast cancer all the trickier.  A Breast Cancer Alphabet is an inspired reaction to what started as a personal predicament.

This A-Z guide to living with breast cancer goes where so many fear to...

Breast Cancer Husband: How to Help Your Wife (and Yourself) during Diagnosis, Treatment and Beyond

Breast Cancer Husband: How to Help Your Wife (and Yourself) during Diagnosis, Treatment and Beyond
by Marc Silver (Author)


A unique guide, like none other on the market-packed with medical information, practical tips, psychological insight, and coping strategies-to help men help the women they love through this trying time.

When Marc Silver became a breast cancer husband three years ago, he learned firsthand how frightened and helpless the breast cancer husband feels. He searched in vain for a book that would give him the information and advice he so desperately sought. Now this award-winning journalist has compiled just the kind of emotionally supportive and useful resource that he wished he had been able to consult-to give men the tools they need to help their wives, their families, and themselves through this scary, uncertain time.

In his years as a consumer journalist and veteran of the News...

The Silver Lining: A Supportive and Insightful Guide to Breast Cancer

The Silver Lining: A Supportive and Insightful Guide to Breast Cancer
by Hollye Jacobs RN MS MSW (Author), Elizabeth Messina (Author)


A NEW YORK TIMES BESTSELLER

As a healthy, happy thirty-nine-year-old mother with no family history of breast cancer, being diagnosed with the disease rocked Hollye Jacobs’s world. Having worked as a nurse, social worker, and child development specialist for fifteen years, she suddenly found herself in the position of moving into the hospital bed. She was trained as a clinician to heal. In her role as patient, the healing process became personal.

Exquisitely illustrated with full-color photographs by Hollye’s close friend, award-winning photographer Elizabeth Messina, The Silver Lining is both Hollye’s memoir and a practical, supportive resource for anyone whose life has been touched by breast cancer. In the first section of each chapter, she describes with humor and...

Breast Cancer: 50 Essential Things to Do

Breast Cancer: 50 Essential Things to Do
by Greg Anderson (Author), Erica A. Harvey (Introduction), Christine Northrup MD (Introduction)


2.5 million women in the U.S. have had a breast cancer diagnosis; more than 200,000 women are diagnosed each year. While recovery and survival rates have improved, selecting a treatment plan can be confusing and overwhelming.Breast Cancer: 50 Essential Things You Can Do offers a roadmap for women facing breast cancer. Cancer-survivor Greg Anderson, a recognized pioneer in the field of integrated cancer care, has guided tens-of-thousands of cancer patients to health and healing over the past 25 years, through his books and his Cancer Recovery Foundation. In this new book he offers critical information about the major issues patients face following a breast cancer diagnosis, and shows how to implement a comprehensive recovery plan that maximizes opportunity for healing and recovery.This is...

© 2014 BrightSurf.com