Princeton Scientists Find Way To Catalog All That Goes Wrong In A Cancer Cell

A team of Princeton University scientists has produced a systematic listing of the ways a particular cancerous cell has “gone wrong,” giving researchers a powerful tool that eventually could make possible new, more targeted therapies for patients.

A team of Princeton University scientists has produced a systematic listing of the ways a particular cancerous cell has “gone wrong,” giving researchers a powerful tool that eventually could make possible new, more targeted therapies for patients.

Saeed Tavazoie is a professor in the Princeton University Department of Molecular Biology & the Lewis-Sigler Institute for Integrative Genomics

“For a very long time, cancer therapies have been developed by trial and error to essentially kill a broad variety of rapidly dividing cells, good and bad — that’s why they have massive side effects,” said Saeed Tavazoie, a professor in the Department of Molecular Biology and the Lewis-Sigler Institute for Integrative Genomics, who led the research. “The goal of cancer biology is to come up with therapies that are much more rational in terms of attacking the pathways that have been co-opted by cancer cells. The big challenge is to discover these pathways so that we can restore them to their normal state.”

Writing in the Dec. 11 issue of Molecular Cell, Tavazoie, along with his colleagues Hani Goodarzi, a graduate student in molecular biology, and Olivier Elemento, a former postdoctoral researcher in the department, found they were able to systematically categorize and pinpoint the alterations in cancer pathways and to reveal the underlying regulatory code in DNA. Elemento is now on the faculty of Weill Cornell Medical College in New York.

“We are discovering that there are many components inside the cell that can get mutated and give rise to cancer,” Tavazoie said. “Future cancer therapies have to take into account these specific pathways that have been mutated in individual cancers and treat patients specifically for that.”

The researchers developed an algorithm, a problem-solving computer program that sorts through the behavior of each of 20,000 genes operating in a tumor cell. When genes are turned “on,” they activate or “express” proteins that serve as signals, creating different pathways of action. Cancer cells often act in aberrant ways, and the algorithm can detect these subtle changes and track all of them.

“At the present moment, we lump a lot of cancers together and use the same therapy,” Tavazoie said. “In the future, we are aiming to be much more precise about treating the exact processes that were perturbed by the mutations.”

Pathologists presently examining the tumors of sick patients analyze a small set of tumor characteristics in order to determine the diagnostic and prognostic class to which the cells belong. This new method could give practitioners an encyclopedic accounting of the alterations in problem cells, spelling out the nature of the disease in much greater detail.

The algorithm devised by the group scans the DNA sequence of a given cell — its genome — and deciphers which sequences are controlling what pathways and whether any are acting differently from the norm. By deciphering the patterns, the scientists can conjure up the genetic regulatory code that is underlying a particular cancer.

The scientists developed the technique by employing modern methods of systems biology, where researchers seek to understand how components of living systems like cells work together to orchestrate processes, using powerful computers to sort vast arrays of data.

“Part of the promise of genomics and systems biology is the discovery of specific pathways of disease and finding ways to target them precisely,” Tavazoie said. “We have focused on revealing what these pathways are.”

The challenge for others, he said, will be to design specific therapies for such diseases, a process that could take many years. “This is an important first step,” Tavazoie added.

The method ultimately could work for any type of cancer and paves the way for rational approaches to treating a host of other diseases from diabetes to neurological disorders, the scientists said.

The research was funded by the National Human Genome Research Institute of the National Institutes of Health.

Sources:

• Princeton scientists find way to catalog all that goes wrong in a cancer cell, News At Princeton, Princeton University, December 10, 2009.

• Goodarzi H, Elemento O, Tavazoie S. Revealing Global Regulatory Perturbations Across Human Cancers. Molecular Cell, Vol. 36, Issue 5, pp. 900-911, December 11, 2009.

Making A Difference: L’Oréal Paris Honors Women of Worth at Special Ceremony in New York City

L’Oréal Paris Honors Women of Worth at Special Ceremony in New York City. Ten Women Recognized for Making a Difference in their Communities with Special Guests including Mary J. Blige, Holly Robinson Peete and Erica Hill.  Shannon Lambert Named Women of Worth National Honoree by Public Vote

L'Oréal Paris' 2009 Women of Worth Honorees with Mary J. Blige, L'Oréal Paris President Karen T. Fondu and Senior Vice President of Marketing Anne Talley at the CNN Inspire Summit.

L'Oréal Paris President, Karen T. Fondu, with Mary J. Blige at the CNN Inspire Summit in New York City.

L’Oréal Paris’ fourth annual Women of Worth program honored ten women for their exceptional achievements and tireless volunteerism efforts at the CNN Inspire Summit in New York City. The event was held December 8th in celebration of the ten 2009 L’Oréal Paris Women of Worth honorees and featured an awards presentation by Karen T. Fondu, President, L’Oréal Paris Division. Special guests speakers included, Mary J. Blige, Holly Robinson Peete, and Erica Hill. The Women of Worth honorees represent a wide range of causes including education, female and youth empowerment, military support and healing for survivors of cancer and sexual violence. Each of the ten honorees received $5,000 from L’Oréal Paris for their charitable organizations, plus a $5,000 matching donation made in their name to the Ovarian Cancer Research Fund, the twelve-year charitable partner of L’Oréal Paris.

Women of Worth Program

The Women of Worth initiative celebrates women who passionately embody the spirit of volunteerism. The initiative empowers and celebrates women everywhere and brings the L’Oréal Paris “Because I’m Worth It” philosophy to life.

“We are so honored to welcome each of the 2009 Women of Worth honorees to this very special community,” said Karen T. Fondu, President, L’Oréal Paris Division. “Each of these amazing women embodies the L’Oréal Paris philosophy and supports our unwavering belief in every woman’s worth and in her power to make a difference in the world.”

Women of Worth Honorees

The ten 2009 L’Oréal Paris Women of Worth honorees are dedicated to a range of causes and are phenomenal examples of the power of volunteerism. Each honoree is an extraordinary community leader representing and inspiring women all across America.

• Brittany Berquist, Norwell, MA, established Cell Phones for Soldiers, Inc. to keep toxic waste out of landfills and provide phone cards for troops serving throughout the world.

• Lillian Collins – Clinton, OK, founded Eastside Academy to assist African American children who need help in reading and math, providing a positive after-school program.

• Anne Ginther – Sammamish, WA, founded RandomKid, which provides staff and services to youth of all backgrounds and abilities for the development, management and accomplishment of their goals to help others.

• Maimah Karmo – Aldie, VA, established Tigerlily Foundation, which provides meals, financial assistance, empowerment and inspiration to younger women affected by breast cancer.

• Shannon Lambert, Minneapolis, MN, founder of Pandora’s Project, a community where women who have survived rape can connect and support one another.

• Brenda Murray – Chevy Chase, MD, has been transforming conditions and providing educational opportunities for thousands of women behind bars for the past 20 years.

• Ora Rakestraw – Sacramento, CA, tutors third graders with special needs, helping these young people have a chance to experience success and stay committed to their education.

• Carol Reza – Whitter, CA, founded Bridge of Faith to provide families of incarcerated women with mentoring and social service referral services.

• Halle Tecco – San Francisco, CA, created Yoga Bear, an organization that provides free yoga classes to cancer patients.

• Rhonda Ulmer – Denton, MD, provides local community resources to parents in her school to obtain their GED, housing, food and health assistance, transforming the school into the hub of the community.

The Women of Worth honorees were chosen from nearly 2,500 applicants by an elite group of judges, which includes Jacqueline Hernandez, Chief Operating Officer of Telemundo Communications Group; Soledad O’Brien, CNN Anchor; Dayle Haddon, L’Oréal Paris spokesperson; Elizabeth Howard, former Chief Executive Officer of the Ovarian Cancer Research Fund; Cindy Kerr, Founder and President of ConKerr Cancer and Anne Talley, Senior Vice President of Marketing for L’Oréal Paris.

Women of Worth National Honoree

Shannon Lambert, founder of Pandora’s Project, a community where women who have survived rape can connect and support one another.

The National Honoree, Shannon Lambert, recognized for her work with Pandora’s Project, which provides support, information and resources to sexual violence survivors received an additional $25,000 from L’Oréal Paris as a result of a national online vote at womenofworth.com.

“My own experience inspired me to create an innovative way for survivors of sexual violence to connect with each other and find the resources they need and deserve to heal.” — Shannon Lambert

It is estimated that at least one in six individuals will experience rape or sexual abuse in their lifetime, and for many, the aftermath of sexual violence is isolating and devastating. Pandora’s Project offers an online resource moderated by a team of volunteers that provides peer-to-peer support for male and female victims of sexual violence. The organization also operates a free sexual assault lending library, maintains resource lists for those in need of face-to-face support, and organizes retreat weekends for women ready to take their healing one step farther.

“I am delighted to be honored as a L’Oréal Paris Woman of Worth,” said Lambert. “The support L’Oréal Paris has given to Pandora’s Project will enable us to continue to help victims of sexual violence and to support their recovery.”

For more information about the Women of Worth program and honorees, please visit womenofworth.com.

About L’Oréal Paris

The L’Oréal Paris division of L’Oréal USA, Inc. is a total beauty care company that combines the latest in technology with the highest in quality for the ultimate in luxury beauty at mass. The L’Oréal Paris brand encompasses the four major beauty categories – haircolor, haircare, skincare and cosmetics – and includes such well-known brands as Preference, Excellence and Féria haircolors; EverPure, VIVE Pro, Studio Line and L’Oréal Kids haircare; Revitalift, Age Perfect, Skin Genesis, Collagen, Sublime Bronze and Men’s Expert skincare; and the Colour Riche, True Match, Infallible, Bare Naturale and HIP High Intensity Pigments cosmetics collections, along with a portfolio of mascara including Voluminous, Double Extend and Telescopic among many others.

L’Oréal Paris is dedicated to women around the world and the company has been inspired to give back and make a difference in their lives. In 1997, L’Oréal Paris made a long-term commitment to raising awareness for ovarian cancer, which continues to build. To date, L’Oréal Paris has helped raise over $18 million dollars to further research and build awareness with fundraising efforts such as the L’Oréal Legends Gala and L’Oréal’s annual “Color of Hope” cosmetics collection.

Source:  L’Oréal Paris Honors Women of Worth at Special Ceremony in New York City, Press Release, L’Oréal Paris, December 9, 2009.

MAGP2 Gene Expression Signature: A Potential Ovarian Cancer Personalized Treatment Target

A multi-institutional study has identified a potential personalized treatment target for the most common form of ovarian cancer. In the December 8 issue of Cancer Cell, the research team describes finding that a gene called MAGP2 – not previously associated with any type of cancer – was overexpressed in papillary serous ovarian tumors of patients who died more quickly. They also found evidence suggesting possible mechanisms by which MAGP2 may promote tumor growth.

A multi-institutional study has identified a potential personalized treatment target for the most common form of ovarian cancer. In the December 8 issue of Cancer Cell, the research team describes finding that a gene called MAGP2 (microfibril-associated glycoprotein 2) – not previously associated with any type of cancer – was overexpressed in papillary serous ovarian tumors of patients who died more quickly. They also found evidence suggesting possible mechanisms by which MAGP2 may promote tumor growth.

Michael Birrer, MD, Ph.D., Professor, Department of Medicine, Harvard Medical School; Director GYN/Medical Oncology, Medicine, Massachusetts General Hospital

“Ovarian cancer is typically diagnosed at an advanced stage when it is incurable, and the same treatments have been used for virtually all patients,” says Michael Birrer, MD, PhD, director of medical gynecologic oncology in the Massachusetts General Hospital (MGH) Cancer Center, and the study’s corresponding author. “Previous research from my lab indicated that different types and grades of ovarian tumors should be treated differently, and this paper now shows that even papillary serous tumors have differences that impact patient prognosis.” Birrer was with the National Institutes of Health when this study began but later joined the MGH Cancer Center.

The fifth most common malignancy among U.S. women, ovarian cancer is expected to cause approximately 15,000 deaths during 2009. Accounting for 60 percent of ovarian cancers, papillary serous tumors are typically diagnosed after spreading beyond the ovaries. The tumors typically return after initial treatment with surgery and chemotherapy, but while some patients die a few months after diagnosis, others may survive five years or longer while receiving treatment.

To search for genes expressed at different levels in ovarian cancer patients with different survival histories, which could be targets for new treatments, the researchers conducted whole-genome profiling of tissue samples that had been microdissected – reducing the presence of non-tumor cells – from 53 advanced papillary serous ovarian cancer tumors. Of 16 genes that appeared to have tumor-associated expression levels, MAGP2 had the strongest correlation with reduced patient survival.

Further analysis confirmed that MAGP2 expression was elevated in another group of malignant ovarian cancer tumors but not in normal tissue. MAGP2 gene expression was also reduced in patients whose tumors responded to chemotherapy. Recombinant expression of MAGP2 in samples of the endothelial cells that line blood vessels caused the cells to migrate and invade normal tissue.  In addition, MAGP2 gene overexpression increased microvessel density — a measurement used to determine the extent of tumor angiogenesis. The latter two observations suggest a potential role for MAGP2 gene overexpression in the growth of an ovarian cancer tumor’s blood supply.

“By confirming that different ovarian tumors have distinctive gene signatures that can predict patient prognosis, this study marks the beginning of individualized care for ovarian cancer,” says Birrer, a professor of Medicine at Harvard Medical School. “MAGP2 and the biochemical pathways it contributes to are definitely targets for new types of therapies, and we plan to pursue several strategies to interfere with tumor-associated pathways. But first we need to validate these findings in samples from patients treated in clinical trials.”

About The Study

Co-lead authors of the Cancer Cell paper are Samuel Mok, M.D., M.D. Anderson Cancer Center, and Tomas Bonome, National Cancer Institute (NCI). Additional co-authors are Kwong-Kowk Wong, M.D. Anderson; Vinod Vathipadiekal, Aaron Bell, Howard Donninger, Laurent Ozbun, Goli Samimi, John Brady, Mike Randonovich, Cindy Pise-Masison, and Carl Barrett, NCI; Michael Johnson, Dong-Choon Park, William Welch and Ross Berkowitz, Brigham and Women’s Hospital; Ke Hao and Wing Wong, Harvard School of Public Health; and Daniel Yip, University of South Florida. The study was supported by grants from the National Institutes of Health, the Ovarian Cancer Research Fund and the National Cancer Institute.

About Massachusetts General Hospital

Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $600 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, systems biology, transplantation biology and photomedicine.

Sources:

• Possible ovarian cancer treatment target identified – Genetic signature associated with poor prognosis could lead to improved therapies, Press Release, Massachusetts General Hospital (via EurekAlert), December 8, 2009.

• Mok SC, Bonome T, Vathipadiekal V, Bell A, Johnson ME, Wong KK, et. al. A gene signature predictive for outcome in advanced ovarian cancer identifies a survival factor: microfibril-associated glycoprotein 2. Cancer Cell. 2009 Dec 8;16(6):521-32. PubMed PMID: 19962670.

• Farley J, Ozbun LL, Birrer MJ. Genomic analysis of epithelial ovarian cancer. Cell Res. 2008 May;18(5):538-48. Review. PubMed PMID: 18427574.

OU’s Non-Toxic Drug Makes Ovarian Cancer Cells Respond To New Treatment & Undergo Cell Suicide

“Cancer researchers at the University of Oklahoma Health Sciences Center have found a way to turn ineffective new cancer drugs into cancer-fighters. By using their patented chemical compound, SHetA2, researchers tricked cancer cells into responding to new treatments and undergoing cell suicide. … [T]he compound will work with several cancers, including lung, kidney, ovarian, colon and pancreatic cancer. … [The] research team … patented the SHetA2 Flex-Het and hope[s] to start clinical trials for the compound within a year. …“

Cancer researchers at the University of Oklahoma Health Sciences Center have found a way to turn ineffective new cancer drugs into cancer-fighters. By using their patented chemical compound, SHetA2, researchers tricked cancer cells into responding to new treatments and undergoing cell suicide. The research appears in the journal Gynecologic Oncology.

Doris Mangiaracina Benbrook, Ph.D., is in her lab at the University of Oklahoma Health Sciences Center in Oklahoma City. (Photo: Univ. of Oklahoma Health Sciences Center)

“This discovery means that we can use our non-toxic cancer prevention pill to improve treatment for people who already have cancer,” said Doris Mangiaracina Benbrook, Ph.D., principal investigator on the project. “All studies to date have not found any side effects of taking our drug, giving hope that we can prevent cancer in healthy people, and improve treatment for cancer patients, without increasing toxicity.”

The latest study looked at an upcoming class of cancer treatment drugs that worked well in experimental models, but proved ineffective against many human tumors. Dr. Benbrook and her team decided to test their compound’s ability to “fix” the problem. It worked.

“The new chemotherapy drugs are antibodies that bind to cell surface receptors called ‘Death Receptors.’ The binding of the antibodies activates the death receptors in cancer cells and causes cell suicide with little harm to normal cells. Many cancers, however, are resistant to the antibodies,” Benbrook said. “We’ve shown that SHetA2 treatment can make ovarian and kidney cancer cells sensitive to the death receptor antibodies and kill the cancer.”

Benbrook said the compound will work with several cancers, including lung, kidney, ovarian, colon and pancreatic cancer.

“It would be a significant advancement in health care if we could avoid the severe toxicity and suffering that late stage cancer patients have to experience,” Benbrook said.

The synthetic compound, SHetA2, a Flex-Het drug, was created by Benbrook with the help of chemist Darrell Berlin at Oklahoma State University. The compound directly targets abnormalities in cancer cell components without damaging normal cells. The disruption causes cancer cells to die and keeps tumors from forming.

Flex-Hets or flexible heteroarotinoids are synthetic compounds that can change certain parts of a cell and affect its growth. Benbrook and her research team have patented the SHetA2 Flex-Het and hope to start clinical trials for the compound within a year. If the compound continues to be found safe, it would be developed into a pill to be taken daily like a multi-vitamin to prevent cancer. This new discovery means that the pill also could be used to make patients, who already have cancer, better respond to treatment.

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Sources:

• OU Cancer Study Takes Major Step Toward Improved Treatment, Press Release,  Health Sciences Center, University of Oklahoma, December 1, 2009.

• Moxley KM, Chengedza S, Mangiaracina D. Induction of death receptor ligand-mediated apoptosis in epithelial ovarian carcinoma: The search for sensitizing agents. Gynecol Oncol. 2009 Dec;115(3):438-42. Epub 2009 Oct 4.PubMed PMID: 19804900; PubMed Central PMCID: PMC2783732.

MIT Develops New Platinum Compound As Powerful As Cisplatin But Better Able To Destroy Tumor Cells

MIT chemists have developed a new platinum compound that is as powerful as the commonly used anticancer drug cisplatin but better able to destroy tumor cells.

A diagram of cisplatin which is a platinum chemotherapy drug.

Massachusetts Institute of Technology chemists have developed a new platinum compound that is as powerful as the commonly

Stephen J. Lippard Ph.D., Arthur Amos Noyes Professor of Chemistry, Massachusetts Institute of Technology

used anticancer drug cisplatin but better able to destroy tumor cells.

The new compound, mitaplatin, combines cisplatin with another compound, dichloroacetate (DCA), which can alter the properties of mitochondria selectively in cancer cells. Cancer cells switch their mitochondrial properties to change the way they metabolize glucose compared to normal cells, and DCA specifically targets the altered mitochondria, leaving normal cells intact.

“This differential effect conveys on mitaplatin the ability to kill cancer cells selectively in a co-culture with normal fibroblast cells, the latter being unaffected at the doses that we apply,” says Stephen Lippard, the Arthur Amos Noyes Professor of Chemistry.

How they did it: The chemists designed mitaplatin so that when it enters a cell, it releases cisplatin and two units of DCA by intracellular reduction. Therefore, mitaplatin can attack nuclear DNA with cisplatin and mitochondria with DCA. DCA promotes the release of cell-death-promoting factors from the mitochondria, enhancing the cancer cell-killing abilities of cisplatin.

Next steps: Lippard’s laboratory has shown that in rodents, mitaplatin can be tolerated at much higher doses than cisplatin, and they have begun studies in mice transplanted with human tissues. If those results are promising, the researchers plan more studies for further demonstration of mitaplatin’s ability in cancer therapy.

Sources:

• New platinum compound shows promise in tumor cells, Press Release, Massachusetts Institute of Technology, December 7, 2009.

• Mitaplatin, a potent fusion of cisplatin and the orphan drug dichloroacetate, Shanta Dhar and Stephen Lippard. Proceedings of the National Academy of Sciences, Published online before print, December 10, 2009, doi: 10.1073/pnas.0912276106.