P53 Gene Mutations Found To Play Major Role In Early Cancer

Mutations to a gene called p53 have been linked to half of all cancers, leading to tumor growth and the spread of cancerous cells.

Now, a Cornell-led study identifies for the first time the mechanisms by which p53 controls cell movement and invasion into other areas of the body.

Using cultures of ovarian surface epithelium cells, where ovarian cancer originates, the researchers found that when they inactivated the p53 gene, the cells began to move and invade the underlying gelatinous protein mixture used in the lab that resembles an extracellular tissue environment.

"People thought that cell motility and invasion were part of later stages of cancer, but we show that this characteristic can be found in cells at the very beginning of cancer formation," said Chang-Il Hwang, lead author of the paper recently published in the Proceedings of the National Academy of Sciences and a graduate student in the lab of Cornell biomedical sciences professor and senior author Alexander Nikitin.

Under normal circumstances, p53 regulates the expression of a receptor protein called MET. But when p53 mutates, MET overexpresses, leading to cell movement and invasive growth. The researchers found two distinct pathways by which p53 regulates and suppresses MET.

"One of the next steps is to study ways to inhibit MET," said Hwang. "Our findings support the idea that suppression of MET could be a particularly reasonable and effective approach to controlling cancer carrying p53 mutations. We hope our findings can be generalized into other types of cancer as well."

In tests, the researchers found the p53 and MET network were consistent in both lung and colon cancer.

Mutations of p53 take many forms, with the most common mutation affecting one of the pathways that regulates MET but not the other pathway. By understanding how different p53 mutations affect each of the two pathways, researchers may one day develop individualized cancer therapies by suppressing MET, said Hwang.

"Different p53 mutations may affect the cancer from different angles," he added.

The study was funded by the National Institutes of Health, the Marsha Rivkin Center for Ovarian Cancer, Cornell's College of Veterinary Medicine and the Ovarian Cancer Research Fund.

Cornell

FDA Rejection Of Exelbine For Treating Non-small Cell Lung Cancer Affects ADVENTRX Pharmaceuticals Share Prices

ADVENTRX Pharmaceuticals Inc. (Amex:ANX) Fell hard due to the new about FDA Rejection of New Drug Application For Lung Cancer Treatment; Shares Drop -1.48 (57.87%) @ 11:18AM EDT.

ADVENTRX Pharmaceuticals Inc. will hold a conference call and a webcast;

Conference Call and Webcast

ADVENTRX will hold a conference call on Wednesday, August 10, 2011 beginning at 8:30 a.m. Eastern time to review the developments discussed in this news release and answer questions. Individuals interested in listening to the conference call may do so by dialing (800) 860-2442 for domestic callers, (412) 858-4600 for international callers and requesting the ADVENTRX Pharmaceuticals Update Call, or, from the webcast on the investor relations section of the Company's Web site at www.adventrx.com. A telephone replay will be available for five days approximately one hour after the conclusion of the call by dialing (877) 344-7529 for domestic callers, or (412) 317-0088 for international callers, and entering conference number 10003222. The webcast will be available on the Company's Web site for 30 days following the completion of the call.

Press Release;

SAN DIEGO, Aug. 9, 2011 /PRNewswire/ -- ADVENTRX Pharmaceuticals, Inc. (NYSE Amex: ANX) announced today that it received a complete response letter from the U.S. Food and Drug Administration (FDA) regarding the Company's New Drug Application (NDA) for Exelbine (vinorelbine injectable emulsion) for the treatment of non-small cell lung cancer.

The FDA determined that it could not approve the Exelbine NDA in its present form. In particular, the complete response letter noted that, based on inspections at clinical sites, the authenticity of the drug products used in the pivotal bioequivalence trial (Study 530-01) could not be verified, which placed the results of the trial into question. The letter stated that the bioequivalence trial will need to be repeated to address this deficiency.

In addition, the FDA requested information regarding product quality, or CMC matters. All CMC information requests in the complete response letter were the subject of FDA inquiries from earlier in the review cycle, and the Company had submitted responses to each request prior to receipt of the complete response letter.

"We are disappointed with the FDA's determination and, next week, plan to request a type A meeting to discuss its response. Following that meeting, we will be in a better position to comment on the future of our Exelbine program. However, we believe the authenticity of the drug products used in the pivotal study is verifiable and plan to discuss FDA's concerns in this regard. We also will inquire whether FDA has comments to our previously submitted responses," said Brian M. Culley, Chief Executive Officer of ADVENTRX.

"In the meantime, our resources and focus are on ANX-188 and ANX-514, which we believe are the long-term value drivers for our company. Our cash and equivalents of $40.7 million at July 31, plus cost savings from delaying or potentially discontinuing the Exelbine program, will provide us the capital to continue to advance both of these programs," Mr. Culley added.

The Company believes that FDA's concern over drug product authenticity stems from the procedures used to select testing and reserve samples in Study 530-01 and the availability of testing and reserve samples for inspection. The Company believes the procedures used to select testing and reserve samples in Study 530-01 were adequate to verify the authenticity of the drug products. Of note, Exelbine and the reference product come in different package presentations, require different preparation procedures and have different physical characteristics. Based on the different characteristics between the study drugs, the Company believes it is unlikely that study sites would confuse the two study drugs or fail to recognize which drug was being administered to a patient.

Brain Tumor, Scientists Find Cause Of The Tumors, Gene Mutations.

Scientists from Johns Hopkins University and Duke University have completed a comprehensive map of genetic mutations occurring in the second-most common form of brain cancer, oligodendroglioma. The papers were published the August 4 ahead-of-print issue of the journal Science.
These findings were only possible due to the advancement of science and technology.

"The team used whole genome sequencing technology so that no genes would be excluded, and we found to our surprise that one gene, on chromosome 19, was mutated in six out of the seven initial tumor specimens we sequenced,A mutation frequency of 85 percent is very high." said Hai Yan, MD, PhD, Duke associate professor of pathology and co-corresponding author of the study.

Press release by John Hopkins (the Press release by Duke University is here);

Release Date: 08/04/2011

--Findings reveal cause of the tumors

Johns Hopkins Kimmel Cancer Center scientists have completed a comprehensive map of genetic mutations occurring in the second-most common form of brain cancer, oligodendroglioma. The findings, reported in the Aug. 4 issue of Science, also appear to reveal the biological cause of the tumors, they say.

To create the map, the scientists sequenced protein-coding genes in seven oligodendroglioma tissue samples, and focused attention on recurring mutations in two genes not previously associated with these tumors – CIC and FUBP1. The investigators say that CIC and FUBP1 are known to regulate cell-signaling processes, and CIC mutations have been rarely linked to sarcoma, breast and prostate cancers.

More mutations in the two genes were found in an additional 27 oligodendroglioma samples. In all, two-thirds of the samples studied had CIC and FUBP1 mutations.

“Whenever we find genes mutated in a majority of tumors, it is likely that the pathway regulated by that gene is critical for the development and biology of the tumor,” says Nickolas Papadopoulos, Ph.D., associate professor of oncology at the Johns Hopkins Kimmel Cancer Center.

In brain cancer, the Johns Hopkins investigators say CIC and FUBP1 mutations may be the “missing link” in what scientists describe as a “two-hit” theory of cancer development. The theory is based on the fact that each cell in the human body has two copies of 23 chromosomes containing thousands of protein-producing genes. If a gene on one chromosome is damaged or deleted, the other copy makes up for the loss of protein. But if the second copy fails as well, the cell cannot make the proper protein and may become cancerous.

In oligodendrogliomas, the “first hit” has long been known to occur in regions of chromosome 1 and 19, which fuse together resulting in a loss of many genes on both chromosomes. Up to 70 percent of oligodendroglioma patients have these DNA fusions, and most of them respond better to chemotherapy and radiation than those who lack the deletions in the chromosomes. For more than a decade, researchers have been looking for evidence of a “second hit” in specific mutated genes that allow oligodendrogliomas to develop.

In the current study, the Johns Hopkins investigators found mutations in the remaining copies of the CIC and FUBP1 genes on chromosomes 1 and 19, suggesting that these mutations represent the second hit needed to create cancer.

“Thanks to the Human Genome Project and advances in cancer genome sequencing, a single study can now resolve decade-old questions and reveal the genetics of this brain cancer,” says Kenneth Kinzler, Ph.D., professor and co-director of the Ludwig Center at Johns Hopkins. “Knowing the genetic roadmap of a cancer is the key to attacking it.”

Oligodendrogliomas account for up to 20 percent of brain cancers and more commonly occur in younger people aged 30 to 45. The cancer forms most often in the frontal lobe of the brain in cells that coat neurons. Median survival of 10 years is considered far better than other brain cancers. Oligodendrogliomas are treated initially with surgery, followed by chemotherapy and radiation.

The research team says its next step will be to test whether patients with CIC and FUBP1 mutations have the same favorable prognosis as those who have the chromosome 1 and 19 fusion, says Chetan Bettegowda, M.D., Ph.D., chief resident in the Department of Neurosurgery at Johns Hopkins.

“We can focus now on when these mutations develop during tumor formation, whether they can guide prognosis, and how they might form targets for therapy,” says Bettegowda.

Bettegowda says the gene map uncovered mutations in other genes, such as PIK3CA, which have been well-studied in cancer. It is possible, he says, that oligodendroglioma patients with mutations in PIK3CA or other genes could be enrolled in current clinical trials using experimental therapies that target these mutations.

Funding for the research was provided by the Virginia and D.K. Ludwig Fund for Cancer Research, the Pediatric Brain Tumor Foundation, the Duke Comprehensive Cancer Center Core, the Burroughs Wellcome Fund, the James S. McDonnell Foundation, state funding from Sao Paulo (FAPESP), the National Cancer Institute and National Institutes of Health.

Contributors to the research include Nishant Agrawal, Yuchen Jiao, Mark Sausen, Laura D. Wood, Ralph H. Hruban, Fausto J. Rodriguez, Daniel P. Cahill, Gregory Riggins, Victor Velculescu and Bert Vogelstein of Johns Hopkins; Roger McLendon, Darell Bigner and Hai Yan of Duke University; and Sueli Mieko Oba-Shinjo and Suely Kazue Nagahashi Marie of the University of Sao Paulo, Brazil.

Under agreements between the Johns Hopkins University, Genzyme, Exact Sciences, Inostics, Qiagen, Invitrogen and Personal Genome Diagnostics, Papadopoulos, Vogelstein, Kinzler and Velculescu are entitled to a share of the royalties received by the university on sales of products related to genes and technologies described in this manuscript. Papadopoulos, Vogelstein, Kinzler, and Velculescu are co-founders of Inostics and Personal Genome Diagnostics, are members of their Scientific Advisory Boards, and own Inostics and Personal Genome Diagnostics stock, which is subject to certain restrictions under Johns Hopkins University policy.

Stand Up To Cancer, Where Your Money Goes!

Stand Up To Cancer PI3K Pathway scientists explain their ongoing progress and look towards the future.

If you ever wondered where all the money you donated to Stand Up To Cancer go. Please watch the above video. And if you have not donated yet or want to learn more about Stand Up To Cancer PI3K Pathway, follow the link below.

"Rarely do you see responses with investigational drugs in phase one but with these compounds some very dramatic responses are being seen." - Dr. Lewis C. Cantley SU2C PI3K Dream Team Leader
SU2C, Stand Up To Cancer