Researchers discover genes involved in colorectal cancer

A jumping gene with the fairy tale name "Sleeping Beauty" has helped to unlock vital clues for researchers investigating the genetics of colorectal cancer.

A study published today used the Sleeping Beauty transposon system to profile the repertoire of genes that can drive colorectal cancer, identifying many more than previously thought. Around one third of these genes are mutated in human cancer, which provides strong evidence that they are driver mutations in human tumours.

The collaborative project funded by Cancer Research UK and the Wellcome Trust was led by Dr David Adams from the Wellcome Trust Sanger Institute, and Dr Douglas Winton, of the Cancer Research-UK Cambridge Research Institute.

"These findings, when combined with mutation data from human colon cancers, will drive forward our understanding of the processes that lead to colorectal cancer," says Dr Adams, senior author from the Sanger Institute. "They demonstrate how many genes can contribute to this cancer and how these genes work together in the development of this disease".

The Sleeping Beauty transposon system induces genetic mutations at random, identifying and tagging candidate cancer genes, the drivers that cause colorectal cancer. This system has become critical in uncovering the genetic pathways that cause cancer, and, in this study, the team identify more than 200 genes that can be disrupted in human colorectal cancers.

Colorectal (bowel) cancer is the third most common cancer in the UK, and the second most common cause of cancer deaths after lung cancer; just under 40,000 people were diagnosed with bowel cancer in the UK in 2008 – around 110 people every day – a figure which has shown little improvement over the last decade.

"Our research provides a rich source of candidate genes that represent potential diagnostic, prognostic and therapeutic targets, and defines the breadth of genes that can contribute to cancer of the intestine," says Dr Winton, senior author from the Cancer Research UK Cambridge Research Institute. "It is becoming increasingly clear that cancers are driven by mutations in disparate collections of genes and it is essential that we tease apart the important changes."

Current thinking is that perhaps around 50 major drivers are mutated in any one cancer cell, but the number and identity of all of the cancer drivers, and how many drivers are found in each type of cancer, is largely unknown. By performing screens for cancer genes in the mouse and by then comparing them to data from human tumours the team identified a rich catalogue of new candidate genes helping to refine the genes that genetic pathways that drive bowel cancer development.

"At its heart, cancer is a disease driven by faulty genes," says Dr Lesley Walker, director of cancer information at Cancer Research UK. "Research suggests that each cancer cell has a number of 'driver' faults that make them grow out of control, as well as 'passenger' faults that they pick up as the disease develops. This technique is helping us to tease out the key drivers of bowel cancer, laying the foundations for more effective, targeted treatments for the disease in the future."

The research complements studies by The Cancer Genome Atlas and the International Cancer Genome Consortium, which are cataloguing the mutations responsible for cancer development using next generation DNA sequencing.

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New lung cancer gene found

A major challenge for cancer biologists is figuring out which among the hundreds of genetic mutations found in a cancer cell are most important for driving the cancer’s spread.

Using a new technique called whole-genome profiling, MIT scientists have now pinpointed a gene that appears to drive progression of small cell lung cancer, an aggressive form of lung cancer accounting for about 15 percent of lung cancer cases.

The gene, which the researchers found overexpressed in both mouse and human lung tumors, could lead to new drug targets, says Alison Dooley, a recent PhD recipient in the lab of Tyler Jacks, director of MIT’s David H. Koch Institute for Integrative Cancer Research. Dooley is the lead author of a paper describing the finding in the July 15 issue of Genes and Development.

Small cell lung cancer kills about 95 percent of patients within five years of diagnosis; scientists do not yet have a good understanding of which genes control it. Dooley and her colleagues studied the disease’s progression using a strain of mice, developed in the laboratory of Anton Berns at the Netherlands Cancer Institute, that deletes two key tumor-suppressor genes, p53 and Rb.

“The mouse model recapitulates what is seen in human disease. It develops very aggressive lung tumors, which metastasize to sites where metastases are often seen in humans,” such as the liver and adrenal glands, Dooley says.

This kind of model allows scientists to follow the disease progression from beginning to end, which can’t normally be done with humans because the fast-spreading disease is often diagnosed very late. Using whole-genome profiling, the researchers were able to identify sections of chromosomes that had been duplicated or deleted in mice with cancer.

They found extra copies of a few short stretches of DNA, including a segment of chromosome 4 that turned out to include a single gene called Nuclear Factor I/B (NFIB). This is the first time NFIB has been implicated in small cell lung cancer, though it has been seen in a mouse study of prostate cancer. The gene’s exact function is not known, but it is involved in the development of lung cells.

Researchers in Jacks’ lab collaborated with scientists in Matthew Meyerson’s lab at the Dana-Farber Cancer Institute and the Broad Institute to analyze human cancer cells, and found that NFIB is also amplified in human small cell lung tumors.

That makes a convincing case that the gene truly is playing an important role in human small cell lung cancer, says Barry Nelkin, a professor of oncology at Johns Hopkins University School of Medicine, who was not involved in this research.

“The question, always, with mouse models is whether they can tell you anything about a human disease,” Nelkin says. “Some tell you something, but in others, there may be only a similarity in behavior, and the genetic changes are nothing like what is seen in humans.”

The NFIB gene codes for a transcription factor, meaning it controls the expression of other genes, so researchers in Jacks’ lab are now looking for the genes controlled by NFIB. “If we find what genes NFIB is regulating, that could provide new targets for small cell lung cancer therapy,” Dooley says.

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Acupuncture relieves hot flashes from prostate cancer treatment

Acupuncture provides long-lasting relief to hot flashes, heart palpitations and anxiety due to side effects of the hormone given to counteract testosterone, the hormone that induces prostate cancer, according to a study published in the April issue of the International Journal of Radiation Oncology Biology Physics, an official journal of the American Society for Radiation Oncology (ASTRO).

The main treatments for men with metastatic prostate cancer are either surgery or hormone therapy to significantly reduce the level of testosterone in the body. Eliminating testosterone has been proven to keep the cancer in check by starving the cancer of hormones it needs to grow and spread. However, about half of the time, this therapy also causes very uncomfortable hot flashes similar to those women experience during menopause. The main way to combat hot flashes is to take antidepressants, but these drugs can cause side effects of their own, including nausea, dry mouth, sleeplessness, altered appetite and sexual changes.

In a prospective study conducted in the department of radiation oncology and the acupuncture section of New York Methodist Hospital and Weill Cornell Medical College of Cornell University, both in New York, researchers evaluated 14 men who were experiencing hot flashes due to hormone therapy for prostate cancer. Upon enrolling in the study, the men were given a hot flash score (HFS) to evaluate their discomfort from daily hot flashes. The mean initial HFS was 28.3.

Participants then received acupuncture twice a week for 30 minutes at a time for four weeks. Two weeks after receiving acupuncture, their HFS was measured again and had dropped more than half to 10.3. At six weeks post-treatment, their HFS was 7.5. After eight months, the men were evaluated again and their mean HFS was 7.

"Our study shows that physicians and patients have an additional treatment for something that affects many men undergoing prostate cancer treatment and actually has long-term benefits, as opposed to more side effects," Hani Ashamalla, MD, lead author of the study and a radiation oncologist at New York Methodist Hospital, said. "We are now designing a randomized clinical trial to further evaluate acupuncture after prostate cancer treatment. I encourage men suffering this symptom to talk to their doctors about enrolling."

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Pfizer partner Strides nabs FDA plant approval

India's Strides Arcolab got a second key facility approval from the FDA. Its oncology unit won the agency's nod for its new production plant in Bangalore, clearing the way for its partnership with Pfizer to shift into higher gear.

The two companies agreed last year to collaborate on the sale of 40 off-patent injectable drugs, mostly cancer meds. Strides would make the drugs and Pfizer would market them in the U.S. The deal was later expanded to cover other areas, including Japan and Europe.

Strides Vice Chairman Arun Kumar told CNBC India that the company expects FDA approval over the next few weeks for products to be made at its newly approved facilities. Strides has approval apps at the FDA for drugs worth $4 billion to $5 billion, Kumar said.

"With this approval and the recently announced approval for the Sterile Complex, we now look forward to scaling up our specialty business through the launch of highly specialized products for the U.S. market," Venkat Iyer, CEO of the oncology unit, said in a statement. Strides also has a collaboration deal with GlaxoSmithKline, as well as deals with other, smaller companies. But the Pfizer agreement is its biggest, Kumar said. "The Pfizer partnership is the most impactful and meaningful partnership that we have."

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CEL-SCI Corporation Commences Phase III Clinical Trial in Head and Neck Cancer in India

CEL-SCI Corporation announced that it has commenced its global Phase III clinical trial for Multikine^®, the Company's flagship immunotherapy, at the Meenakshi Mission Hospital and Research Centre in Madurai, Tamil Nadu, India, the first clinical site in India. Enrollment is expected to commence in the first half of May. Currently, the study has a US center at Hematology and Oncology Associates in Tupelo, Mississippi, actively recruiting patients. The Company expects enrollment in India to be substantially faster than in North America since head and neck cancer is India's leading cancer. The total study is expected to enroll a total of about 880 head and neck cancer patients in about 48 hospitals in 9 countries on three continents. CEL-SCI's partners Teva Pharmaceuticals and Orient Europharma will conduct parts of the Phase III study in Israel and Taiwan respectively.

The goal of this study is to establish Multikine as a first-line standard of care therapy in treating newly diagnosed, not yet treated head and neck cancer patients. The trial is believed to be the largest head and neck cancer study ever conducted and is called "IT-MATTERS", an acronym for: Immunotherapy Multikine Anti Tumor Treatments.

"We are very excited to begin this pivotal study in the first center outside of the US," said Geert Kersten, Chief Executive Officer of CEL-SCI. "We expect foreign centers to attract a significant number of patients, which will compress the time period necessary to complete the study."

CEL-SCI's Phase III clinical trial is an open-label, randomized, controlled, multi-center study designed to determine if Multikine administered prior to current standard of care (Surgery plus Radiotherapy or Surgery plus Concurrent Radiochemotherapy) used for treatment naive subjects with Advanced Primary Squamous Cell Carcinoma of the Oral Cavity/Soft Palate (Head and Neck cancer) will result in an increased overall rate of survival versus subjects treated with standard of care only. It will also be the first trial in which immunotherapy will be administered before any other traditional means of care are attempted. A detailed description of the study can be found at:http://www.clinicaltrials.gov/ct2/show/NCT01265849?term=multikine&rank=1.

Phase II clinical trials of Multikine demonstrated the product was safe and well-tolerated and eliminated tumors in 12% of subjects, which are the patient population now being selected for the Phase III Study. This was achieved following 3 weeks of treatment, the same treatment regimen that is now used in the Phase III study. The Multikine treatment regimen was also shown to kill, on average, about half of the cancer cells in the subjects' tumors before the start of standard therapy. Follow-up studies of subjects enrolled in the "proof of concept" Phase II trial showed a 33% improvement in the survival rate of those treated with Multikine at a median of three and a half years following surgery. The U.S. Food and Drug Administration granted orphan drug status to Multikine in the neoadjuvant therapy of patients with squamous cell carcinoma of the head and neck.

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