Tag Archives: David Craig

breast.cancer

TGen breast cancer study is journal’s most cited

At its Annual Meeting, the American Association for Cancer Research (AACR) announced that a scientific paper describing potential drug targets following the unprecedented genomic sequencing of 14 metastatic triple-negative breast cancer patients was the most cited study in 2013 of any published that year by AACR’s journal Molecular Cancer Therapeutics.

In the study, genomic sequencing – spelling out the billions of pieces of genetic information in an individual patient’s DNA – revealed therapeutic drug targets for difficult-to-treat, metastatic triple-negative breast cancer (TNBC).

The Translational Genomics Research Institue (TGen), Baylor University Medical Center and US Oncology Research investigators found significant recurring mutations and other changes in more than a dozen genes in patients treated at Baylor University Medical Center at Dallas. In addition, the investigators identified mutations previously unseen in metastatic TNBC and took the sequencing data into account in selection of therapeutic protocols specific to each patient’s genetic profile.

“The nature of this disease cried out for innovative research techniques such as whole genome sequencing coupled with new tools for data analysis,” said Dr. David Craig, Ph.D., TGen’s Deputy Director of Bioinformatics, one of the study’s co-lead authors.

The most frequently mutated gene among the tumors was the TP53 tumor suppressor, and aberrations were observed in additional tumor suppressor genes including CTNNA1, which was detected in two of six African American patients. Alterations were also seen in the ERBB4 gene, known to be involved in mammary-gland maturation during pregnancy and lactation, but not previously linked to metastatic TNBC.

Each tumor was genomically unique, but the majority contained alterations in one or both of the RAS/RAF/MEK/ERK and PI3K/AKT/MTOR pathways. Targeted therapeutic intervention aimed at these pathways achieved antitumor responses in several cases.

“The fact that this study has been cited more often than any other in Molecular Cancer Therapeutics that year is a testament to strong interest the oncology community has in understanding the molecular basis of metastatic TNBC, and in the hypothesis that targeting specific mutations in patients’ TNBCs will improve patients’ outcomes,” said Joyce O’Shaughnessy, M.D., the study’s other co-lead author. Dr. O’Shaughnessy is the Celebrating Women Chair of Breast Cancer Research at Baylor University Medical Center at Dallas, Chair of the US Oncology Network’s Breast Cancer Program, and a practicing oncologist with Texas Oncology.

Metastatic TNBC is a highly aggressive form of breast cancer that does not express the estrogen receptor, progesterone receptor or HER-2, the biomarkers successfully targeted in most breast cancers.

Metastatic TNBC has a poor prognosis with a median survival rate among metastatic patients of only one year. While TNBC accounts for only about 15 percent of all breast cancers, its more aggressive biology makes it responsible for nearly one in four deaths related to this disease.

“This study continues to stand as a great example of molecular medicine in practice. The results have provided novel and interesting clues into breast cancer biology and into the promise and challenges of precision medicine,” said Dr. John Carpten, Ph.D., TGen’s Deputy Director of Basic Science, Director of TGen’s Integrated Cancer Genomics Division, and the study’s senior author.

The study, “Genome and transcriptome sequencing in prospective triple negative breast cancer uncovers therapeutic vulnerabilities,” was conducted by the Translational Genomics Research Institute (TGen) and US Oncology Research with support from Life Technologies Corporation.

Molecular Cancer Therapeutics is one of several peer-reviewed scientific journals published by the 35,000-member American Association for Cancer Research (AACR), the oldest and largest scientific organization in the world focused on every aspect of high-quality, innovative cancer research. The programs and services of the AACR foster the exchange of knowledge and new ideas among scientists dedicated to cancer research, provide training opportunities for the next generation of cancer researchers, and increase public understanding of cancer.

chromosome

TGen uses X chromosome to uncover disorders in girls

Using a basic genetic difference between men and women, the Translational Genomics Research Institute (TGen) has uncovered a way to track down the source of a neurological disorder in a young girl.

TGen’s discovery relies on a simple genetic fact: Men have one X and one Y chromosome, while women have two X chromosomes. This women-only factor was leveraged by TGen investigators to develop a highly accurate method of tracking down a previously unrecognized disorder of the X-chromosome.

The study of a pre-teen girl, who went years with an undiagnosed neurobehavioral condition, was published today in the scientific journal PLOS ONE.

TGen’s findings were made within its Dorrance Center for Rare Childhood Disorders, where investigators and clinicians apply the latest tools of genomic medicine to provide answers for parents seeking to identify the disease or disorder affecting their child.

The scientists sequenced, or spelled out in order, the complete genetic codes of DNA and RNA of the girl. Because girls inherit an X chromosome from each of their parents (boys inherit a Y chromosome from their father), they also sequenced her mother and father. On average, about half of all X chromosomes active in a female come from the mother and the other half from the father.

“We now have the tools to significantly accelerate the diagnostic process, reducing the need for children to undergo multiple tests that can be emotionally and physically taxing for the entire family,” said Dr. David Craig, TGen’s Deputy Director of Bioinformatics, Co-Director of the Dorrance Center and the paper’s senior author.

Sequencing would reveal the proportion of X chromosomes, and if disproportionate, whether the more abundant of the two were damaged in some way, which often leads to X-linked genetic conditions.

“At the time of enrollment, we suspected the girl had a complex neurobehavioral condition, based on her attention deficit, and delays in development and learning,” said Dr. Vinodh Narayanan, Medical Director of the Dorrance Center. “Her brain MRI scans were normal. We needed to find out more — at the genetic level — about what might be causing her disorder.”

By sequencing the DNA and RNA, TGen investigators were able to precisely identify which cells contained active X chromosomes from the girl’s mother, which contained active X chromosomes from the father, in what proportions, and whether they were associated with any known disorders.

They discovered that the X chromosome from the father contained a segment shown to be associated with neurobehavioral conditions. Interestingly, however, the proportion of X chromosomes active in the girl’s cells skewed toward the normal X inherited from her mother. This skewing may have led to a milder, harder to diagnose condition undetected by conventional methods.

“This study shows the power sequencing holds when scanning for potential disease causing and disease-modifying genetic variations,” said Dr. Matt Huentelman, the other Co-Director of the Dorrance Center and an author of the PLOS ONE paper. “I’m most excited to see the pace at which TGen has pushed the genome sequencing technology to where it can help patients — today.”

TGen Research Associate Szabolcs Szelinger, the paper’s lead author, said: “With just a small bio sample, we are now able to provide a comprehensive evaluation of the effects that genetic variation has on patients, leading to highly personalized treatment options, while at the same time providing researchers with insights into the underlying molecular processes.”

Since opening in October 2013, TGen’s Dorrance Center for Rare Childhood Disorders Dorrance Center has enrolled nearly 300 families. And with the rapid decrease in sequencing costs and improved analytical methods, comprehensive, integrative sequencing approaches will likely be used more in the future. Information on the Dorrance Center is available at www.c4rcd.org.

Funding for the study came from the State of Arizona, the Stardust Foundation, and donations to the TGen Foundation.

brain

TGen-Ivy Foundation brain cancer trial approved

In 2012, The Ben & Catherine Ivy Foundation awarded $10 million in grants for two groundbreaking brain cancer research projects at the Translational Genomics Research Institute (TGen). One of those projects has officially received the final regulatory approval from University of California, San Francisco, which means patient enrollment for the trial can begin.

In the $5-million-project, “Genomics Enabled Medicine in Glioblastoma Trial,” TGen and its clinical partners will lead first-in-patient clinical trial studies that will test promising new drugs that might extend the survival of GBM patients. This multi-part study will take place in clinics across the country and TGen laboratories.

“GBM is one of the top three fastest-killing cancers out there and it affects people of all ages,” said Catherine (Bracken) Ivy, founder and president of The Ben & Catherine Ivy Foundation. “It is critical that we fund research that will help patients live longer so we can study and treat brain cancer.”

The project begins with a pilot study of 15 patients, using whole genome sequencing to study their tumor samples to help physicians determine what drugs might be most beneficial.

To support molecularly informed clinical decisions, TGen labs also will examine genomic data from at least 536 past cases of glioblastoma, as well as tumor samples from new cases, developing tools that will produce more insight into how glioblastoma tumors grow and survive. TGen also will conduct a series of pioneering lab tests to measure cell-by-cell responses to various drugs.

“GBM is a disease that needs answers now, and we strongly believe those answers will be found in the genome,” said Dr. David Craig, TGen’s Deputy Director of Bioinformatics, Director of TGen’s Neurogenomics Division, and one of the projects principal investigators. “Identifying the genes that contribute to the survival of glioblastoma will provide valuable information on how to treat it, and may also lead to an improved understanding of what drives other cancers as well.”

To get new treatments to patients as quickly as possible, this five-year study will include a feasibility study involving up to 30 patients, followed by Phase II clinical trials with as many as 70 patients. TGen is teaming with the Ivy Early Phase Clinical Trials Consortium that includes: University of California, San Francisco; University of California, Los Angeles; the MD Anderson Cancer Center; Memorial Sloan Kettering Cancer Center; University of Utah; and the Dana-Farber/Harvard Cancer Center.

The results of these clinical trials should not only help the patients who join them, but also provide the data needed for FDA approval and availability of new drugs that could benefit tens of thousands of brain cancer patients in the future.

“Working with physicians, the project will aim to understand treatment in the context of the tumor’s molecular profile. We will have the opportunity to determine when combinations of drugs might be more effective than using a single drug, quickly identify which therapies don’t work, and accelerate discovery of ones that might prove promising for future development,” said Dr. John Carpten, TGen’s Deputy Director of Basic Science, Director of TGen’s Integrated Cancer Genomics Division, and another of the project’s principal investigators.

In addition to helping patients as quickly as possible, the project should significantly expand Arizona’s network of brain cancer experts.

prevention trial - brain scan images

Ivy Foundation Grants Over $9M for Brain Cancer Research

The Ben & Catherine Ivy Foundation (Ivy Foundation) announced its 2012 grant recipients, which total more than $9 million in funding for brain cancer research. The Ivy Foundation is the largest privately funded brain cancer research foundation in North America. Catherine Ivy is the founder and president of the Ivy Foundation, which has a research funding focus on glioblastoma multiforme (GBM), the most common and deadliest of malignant primary brain tumors in adults.

The Ivy Foundation awarded the following grants and/or provided funding in 2012:

· $2,500,000 over three years:  Principal Investigator, Greg D. Foltz, M.D., Director, The Ben & Catherine Ivy Center for Advanced Brain Tumor Treatment, Swedish Medical Center
· $5,000,000 over five years:  Principal Investigators, John Carpten, Ph.D. and David Craig, Ph.D., Translational Genomics Research Institute (TGen) – a collaborative effort with University of California, San Francisco; University of California, Los Angeles; Memorial Sloan-Kettering Cancer Center; Massachusetts General Hospital; Dana Farber/Harvard Cancer Center; MD Anderson; and University of Utah
· $45,000 annually: Principal Investigator, Brandy Wells, Translational Genomics Research Institute (TGen), for the Ivy Neurological Sciences Internship program
· Over $2 million paid out in 2012 for previously committed multi-year brain cancer research grants

“We are encouraged and remain strongly committed to moving the progress forward for patients diagnosed with brain cancer,” said Ivy. “The 2012 Ivy Foundation grant recipients are important strategic partners in our objective to double the life expectancy of people diagnosed with GBM within the next seven years.”