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CAN TYROSINE SLOW OR STOP CANCER METASTASIS?

Some Tumors Contain Factors That May Block Metastasis

Note: Tyrosine, an amino acid, which can also be synthesized in the body from phenylalanine, is found in many high-protein food products such as soy products, chicken, turkey, fish, peanuts, almonds, avocados, milk, cheese, yogurt, cottage cheese, lima beans, pumpkin seeds, and sesame seeds.  Tyrosine can also be obtained through supplementation. 

ScienceDaily (Nov. 14, 2011) — Scientists are another step closer to understanding what drives tumor metastasis, as laboratory models suggest there are factors inside tumors that can slow their own growth.

In a recent issue of Cancer Research, a journal of the American Association for Cancer Research, Raúl A. Ruggiero, Ph.D., a biological researcher at the division of experimental medicine at the National Academy of Medicine in Buenos Aires, Argentina, described this novel mechanism.

Ruggiero and colleagues used bioanalytical methods of ion electrospray mass and tandem mass spectrometry to identify the factors that lead to metastasis resistance in laboratory models of localized cancer, a phenomenon called "concomitant tumor resistance" in which factors in a tumor can inhibit its own metastasis.

"The main cause of death in cancer patients is associated much more with metastasis rather than with the growth of a localized tumor, which generally can be surgically removed," he said.

Ruggiero's laboratory found that the presence of variant forms of the amino acid tyrosine were responsible for concomitant tumor resistance. In tumor models where these variants of tyrosine were present, the localized tumor did not tend to metastasize as fast as tumors lacking the variants.

Currently, tumor metastasis is treated with various chemotherapy regimens, but Ruggiero said the results of this sort of treatment are usually disappointing. He hopes that these tyrosine variants could be developed as a simple and safe type of therapy to retard metastatic growth.

"Both meta- and ortho-tyrosine have many attractive features. They exert antitumor effects at very low concentrations, are naturally produced in the proper tumor bearing organism, and do not appear to exert any toxic side effects," said Ruggiero. "If these findings are confirmed we could develop new and more harmless means to manage malignant disease."

 

CANCER FIGHTING T-CELLS ACTIVATED BY ARGININE SUPPLEMENT

Arginine restores T-cell ability to target cancer

November 22nd, 2011 in Cancer 

 

In many cases, tumors suppress a patient's immune system in a way that keeps the cancer safe from immune system attack. This is particularly true for patients with glioblastoma, a primary brain tumor that carries a prognosis of only 12-15 months survival after diagnosis.

A study at the University of Colorado Cancer Center, recently published as a featured article in the journal Clinical Cancer Research, shows that treatment with the over-the-counter amino acid arginine may reactivate cancer-fighting T-cells in patients with glioblastoma, thus potentially allowing the immune system to help cleanse the body of cancer.

T-cells are the primary agent responsible for anti-tumor immune responses.

"If you take T-cells from patients with glioblastoma and stimulate them in the lab, they aren't effective (in killing cancer cells)," says lead author Allen Waziri, MD, investigator at the CU Cancer Center, assistant professor of neurosurgery at the University of Colorado School of Medicine. "But when we add back arginine, we restore T-cell function."

In part, function is restored through the activity of neutrophils – an ancient and nonspecific type of white blood cell that kills invaders. After responding to inflammation, neutrophils stop the ongoing immune response. It's as if once they arrive, they consider the infection treated and so suppress any response that exceeds what is needed – a response that if left unchecked would lead to the destruction of healthy tissues.

Neutrophils stop the immune response by secreting an enzyme called arginase. And after they secrete arginase, commonly they die and are excreted by the body. However, in many glioblastoma patients, these neutrophils persist and continue to produce immune-suppressing arginase.

"Persistence of activated neutrophils and increased arginase in the circulation of glioblastoma patients is a fascinating phenomenon, particularly considering that under normal conditions, neutrophils are expected to have an average lifespan of just several hours after activation," he says.

Waziri's group has hypothesized that persistent arginase production from neutrophils suppresses the immune system and keeps cancers from becoming immune targets.

"From one perspective, it appears that glioblastoma is taking advantage of a simple, evolutionarily-ancient method for controlling out-of-control immunity to avoid the specific anti-tumor immune response," Waziri says.

However, there is a step between increased arginase and immune system suppression, and this is where Waziri and colleagues intervene – arginase, in fact, deletes the common amino acid arginine.

T-cells are critically dependent on arginine for activation and function. Therefore, it's not the increase in arginase per se that is responsible for blunting T-cell activity, but rather the resulting lack of arginine that suppresses the immune systems of glioblastoma patients, Waziri's group found.

Waziri and colleagues at the CU Cancer Center recently started a phase 0 clinical trial in newly diagnosed glioblastoma patients to explore whether a week-long, high-dose course of arginine before cancer surgery can allow an immune system that previously missed cancer cells to recognize and attack them. Waziri and his team will look at the effect of arginine on patients' immune systems as measured by T-cell function, immunological profile, and T-cell infiltration into resected tumor tissue.

"Our overall goal is to improve the efficacy of immunotherapy for glioblastoma," he says. "It's likely that this will require a two-stage approach, including stimulation of the immune system with something like a tumor vaccine while simultaneously targeting the suppressive effects of tumors on the immune system."

With positive results from this initial trial, Waziri hopes to further explore whether longer courses of arginine could help reduce the recurrence of glioblastoma and potentially offer a new strategy for patients with this otherwise incurable disease.

Waziri credits seed grants he has received from the AMC Cancer Fund (a fundraising arm of the CU Cancer Center), he Cancer League of Colorado, and an American Cancer Society Institutional Research Grant for contributing to the preclinical work that has led to this exciting clinical trial.

Provided by University of Colorado Denver

 

"Arginine restores T-cell ability to target cancer." November 22nd, 2011. http://medicalxpress.com/news/2011-11-arginine-t-cell-ability-cancer.html

 

VACCINE COULD PREVENT 90% OF ALL CANCER REOCCURENCE

Preface:  You have to be skeptical with news releases like this because of companies trying to pump up initial stock issues.  But this is an encouraging report.  But six years away from implementation?  Hmmm 

Breakthrough: Israel Develops Cancer Vaccine

: Vaxil’s groundbreaking therapeutic vaccine, developed in Israel, could keep about 90 percent of cancers from coming back.

As the world’s population lives longer than ever, if we don’t succumb to heart disease, strokes or accidents, it is more likely that cancer will get us one way or another. Cancer is tough to fight, as the body learns how to outsmart medical approaches that often kill normal cells while targeting the malignant ones.

In a breakthrough development, the Israeli company Vaxil BioTherapeutics has formulated a therapeutic cancer vaccine, now in clinical trials at Hadassah University Medical Center in Jerusalem. If all goes well, the vaccine could be available about six years down the road, to administer on a regular basis not only to help treat cancer but in order to keep the disease from recurring.

The vaccine is being tested against a type of blood cancer called multiple myeloma. If the substance works as hoped — and it looks like all arrows are pointing that way — its platform technology VaxHit could be applied to 90 percent of all known cancers, including prostate and breast cancer, solid and non-solid tumors.

“In cancer, the body knows something is not quite right but the immune system doesn’t know how to protect itself against the tumor like it does against an infection or virus. This is because cancer cells are the body’s own cells gone wrong,” says Julian Levy, the company’s CFO. “Coupled with that, a cancer patient has a depressed immune system, caused both by the illness and by the treatment.”

The trick is to activate a compromised immune system to mobilize against the threat.

A vaccine that works like a drug

A traditional vaccine helps the body’s immune system fend off foreign invaders such as bacteria or viruses, and is administered to people who have not yet had the ailment. Therapeutic vaccines, like the one Vaxil has developed, are given to sick people, and work more like a drug.

Vaxil’s lead product, ImMucin, activates the immune system by “training” T-cells –– the immune cells that protect the body by searching out and destroying cells that display a specific molecule (or marker) called MUC1. MUC1 is typically found only on cancer cells and not on healthy cells. The T-cells don’t attack any cells without MUC1, meaning there are no side effects unlike traditional cancer treatments. More than 90% of different cancers have MUC1 on their cells, which indicates the potential for this vaccine.

“It’s a really big thing,” says Levy, a biotechnology entrepreneur who was formerly CEO for Biokine Therapeutics. “If you give chemo, apart from the really nasty side effects, what often happens is that cancer becomes immune [to it]. The tumor likes to mutate and develops an ability to hide from the treatment. Our vaccines are also designed to overcome that problem.”

For cancers in an advanced stage, treatments like chemo or surgery to remove a large tumor will still be needed, but if the cancer can be brought down to scale, the body is then able to deal with it, Levy explains. ImMucin is foreseen as a long-term strategy — a shot every few months, with no side effects — to stop the cancer from reoccurring after initial treatments, by ensuring that the patient’s own immune system keeps it under control.

In parallel, the company is also working on a vaccine that treats tuberculosis, a disease that’s increasing worldwide, including in the developed world, and for which the current vaccine is often ineffective and treatment is problematic.

Based in Ness Ziona, Vaxil was founded in 2006 by Dr. Lior Carmon, a biotechnology entrepreneur with a doctorate in immunology from the Weizmann Institute of Science in Rehovot. In June, Vaxil signed a memorandum of understanding to merge its activities into Sheldonco, a company traded on the Tel Aviv Stock Exchange.

By Rivka Borochov

 

SLEEPING BEAUTY GENE UNLOCKS NIGHTMARE OF COLON CANCER

Researchers discover genes involved in colorectal cancer

November 6th, 2011 in Genetics 

 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 humancolorectal 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.

More information: Nature Genetics doi: 10.1038/ng.990