Viral therapy could boost limb-saving cancer treatment

Viruses designed to target and kill cancer cells could boost the effectiveness of chemotherapy to the arms and legs and help avoid amputation, a new study reports.

Scientists at The Institute of Cancer Research, London, tested the effectiveness of a genetically engineered version of the virus used to vaccinate against smallpox. They found use of the virus alongside isolated limb perfusion chemotherapy – given directly to blood vessels supplying the affected arm or leg as an alternative to amputation – was more effective in rats than either treatment on its own.

The study, published in the International Journal of Cancer, was funded by the Dr Lucy M Bull Lectureship and Research Fund and supported by the NIHR Biomedical Research Centre at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research (ICR), with additional funding from The Royal College of Surgeons of England and Sarcoma UK.

Researchers at the ICR, in collaboration with colleagues at The Royal Marsden, used a vaccinia virus known as GLV-1h68. This virus had been modified to infect and kill cancer cells.

The study suggests that the combination, if successful in the clinic, could help some skin cancer and sarcoma patients avoid radical surgery or amputation, greatly improving their quality of life. A clinical trial to test the combination in cancer patients has now been approved and is expected to take place in the near future.

Isolated limb perfusion uses a heart and lung bypass machine connected to the arm or leg to separate its blood supply from the rest of the body. This allows a high dose of a chemotherapy drug (in this case melphalan) to be given directly and specifically to the diseased limb without causing toxic side-effects to the rest of the body.

Chemotherapy is given alongside a drug called tumour necrosis factor-alpha (TNF-α) which helps make blood vessels more leaky, allowing melphalan to get to the tumour more effectively. In this study, researchers found that TNF- α also helped the virus get to the tumour more easily.

Researchers first tested the treatments on rat sarcoma cells in tissue culture, and found combining modified vaccinia virus and melphalan killed more cells than either treatment on its own.

They tested the combination in rats with advanced sarcoma and found it slowed tumour growth and prolonged survival by 50% compared to standard ILP therapy (melphalan and TNF-α). Rats given the combined therapy survived a median of 24 days, compared to 16 days for rats who received standard limb perfusion treatment, 15 days with the modified virus alone, and 11 days with no treatment. They saw the modified virus had no adverse effects on the rats, adding to existing evidence that the virus has a good safety profile.

Isolated limb perfusion allows drugs to be given in much higher doses than could be tolerated by the whole body. It is used by doctors as a last line of treatment for advanced skin cancer or sarcomas in the hope of avoiding amputation. However, the technique is not always successful and researchers have been searching for ways to make the approach more effective.

Professor Kevin Harrington, Professor of Biological Cancer Therapies at The Institute of Cancer Research, London, and Honorary Consultant at The Royal Marsden NHS Foundation Trust, said: “Our research shows that a virus that targets and kills cancer cells could significantly improve an existing treatment for advanced skin cancer and sarcoma in the arms and legs. Combining modified virus and isolated limb chemotherapy doubled survival times in the laboratory, which gives us hope that it might be effective in the clinic. We have approval to start clinical trials on the combination therapy and hope to begin testing in patients in the near future.”

The beauty of this technique is that the arm or leg is isolated, making it harder for the virus to be destroyed by the immune system – something that has been a stumbling block for virus treatments in the past. The study also showed that the virus didn’t cause any adverse effects, adding to evidence that it should be safe to use as a cancer treatment.

Professor Paul Workman, Deputy Chief Executive of The Institute of Cancer Research, London, said: “Viral therapies have been suggested as a possible treatment for cancer for a number of years, but trials of cancer-killing viruses alone have not proved effective enough. Combining cancer-killing viruses with chemotherapy gives the tumour a double hit that could offer an improvement over existing treatment, and might help cancer patients avoid amputation.”

Pencavel et al., (2014). Isolated limb perfusion with melphalan, tumour necrosis factor-alpha and oncolytic vaccinia virus improves tumour targeting and prolongs survival in a rat model of advanced extremity sarcoma.  Int. J. Cancer, EPub Ahead of Print, doi: 10.1002/ijc.29059  [Abstract]

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Unique study focuses on combined treatment approach for locally advanced pancreatic cancer

The study and accompanying clinical trial aim to identify tumor biomarkers and provide clues into individual treatment response

Investigators at the Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute are developing a novel, multistep investigational treatment for one of the most complex and difficult-to-treat forms of the disease, locally advanced pancreatic cancer.

Locally advanced pancreatic cancer has the lowest survival rate of any solid tumor, with a cumulative five-year survival rate of only 4 percent for all stages of disease. Surgery is rarely an option for patients because tumors often involve vital blood vessels. Chemotherapy and radiotherapy given concurrently remain the mainstay treatment, yet to-date, no treatment has had a significant impact on improving outcomes.

To move the needle forward toward prolonged survival and better treatment outcomes, our research team created a combined investigational regimen for patients with locally advanced pancreatic cancer,” said Richard Tuli, MD, PhD, a radiation oncologist in the Department of Radiation Oncology and a member of the Samuel Oschin Comprehensive Cancer Institute. “Coupled with this research treatment, we are also looking to identify patient biomarkers, or molecular signatures, that may provide clues to how, and why, some patients respond better than others.”

Tuli was the first author of a pre-clinical study recently published in the journal Translational Oncology. Using animal models, the study evaluated a novel treatment for pancreatic cancer that combines radiation, chemotherapy and treatment with a specific drug that can inhibit the repair of cancer cells damaged by chemotherapy and radiation. Successful research findings led to a clinical trial now enrolling eligible patients.

Many standard cancer treatments for pancreatic cancer, including chemotherapy and radiation therapy, kill tumors by damaging their DNA. When such DNA damage occurs, proteins known as PARPs move to the site of damage and begin to mend these broken strands of DNA, allowing cancerous cells and tumors to recover, grow and proliferate, thereby escaping the effects of treatment.

With this knowledge, researchers combined radiation with a drug to prevent PARP from repairing cancerous cells. When the treatment was given to laboratory mice, the combination resulted in prolonged survival.

Based on this research, we are now conducting a first-in-human study combining the PARP inhibitor with radiation and chemotherapy in patients with locally advanced pancreatic cancer, with an ultimate goal of improving survival rates and treatment outcomes,” said Tuli.

The investigational treatment regimen also could prove beneficial to patients with other forms of cancer. Recent research findings suggest PARP could be beneficial for patients who carry either or both the BRCA1 or BRCA2 mutations. “Normal” BRCA genes help suppress tumor formation and repair damaged DNA; the mutated genes’ protective mechanisms are compromised, leading to genetic defects that result in cancer. But the “defective” repair capability is a process that may be exploited by treatments, such as PARP inhibition, which further impairs the ability of tumors to repair their own DNA after insult with radiation.

In addition to adding a novel PARP inhibitor to the regimen, investigators are seeking to identify other markers related to DNA damage that could provide a molecular signature, or biomarker, to forecast how a patients’ tumor would respond to treatment and help guide personalized treatment options in the near future.

Identifying individual biomarkers to better understand how a patient may respond to treatment is an essential step toward personalizing medicine for every individual,” said Steven Piantadosi, MD, PhD, director of the Samuel Oschin Comprehensive Cancer Institute and Phase One Foundation Chair. “It is the goal of our cancer institute to combine the most advanced patient-centered clinical care with innovative research that expands treatment options and improves outcomes. This is especially true in pancreatic cancer, which has been long known as a challenging disease to fight.”

Tuli et al., (2014). Radiosensitization of Pancreatic Cancer Cells In Vitro and In Vivo through Poly (ADP-ribose) Polymerase Inhibition with ABT-888. Transl Oncol., EPub Ahead of Print [Abstract]

Increased overall survival for advanced stage non-small cell lung cancer patients is associated with availability of less toxic chemotherapy

A 10-year population-based study shows that increased availability of better systemic chemo- and targeted-therapies for patients with advanced non-small cell lung cancer (NSCLC) coincides with increased usage of these therapies. This in turn leads to a significant increase in overall survival.

Researchers from the British Columbia Cancer Agency, Vancouver, Canada, performed a retrospective chart review of all patients referred to the agency with advanced stage (IIIB or IV) lung cancer and grouped the patients into 4 one-year time frame cohorts; one termed “baseline” and three other groups that each started 6-months after a new second-line agent (docetaxel, erlotinib and pemetrexed) was made commercially available and put into practice. In British Columbia, Canada, the implementation of the second-line agents docetaxel, erlotinib and pemetrexed occurred in December 2000, October 2005 and June 2007, respectively. Cohort 1 (January to December 1998) with 555 patients was the baseline and cohort 2 (May 2001-April 2002) had 613 patients, cohort 3 (March 2006-February 2007) had 688 patients and Cohort 4 (November 2007-Ocotober 2008) had 750 patients.

The results published in the August Issue of the Journal of Thoracic Oncology, the official journal of the International Association for the Study of Lung Cancer, show that the usage of second-line therapy increased significantly over time. At baseline only 21% of the patients received second-line therapy but in Cohorts 2 and 3 this increased to 27% and 37% respectively, and by Cohort 4 more than half, 55%, received second-line therapy. The most common agent in Cohort 1 was docetaxel (48%) but by Cohort 4 erlotinib (EGFR TKIs) and pemetrexed were used 50% and 26% of the time. The research also found that the proportion of patients who received at least first-line systemic chemotherapy also increased over the four time points from 16% in Cohort 1 to 23%, 34% and 33% for Cohorts 2-4, respectively.

The median overall survival of the patients who did not receive any chemotherapy did not change over the four time points; 3.9, 4.0, 3.1 and 3.2 months (p=0.136), however for those that did receive chemotherapy survival increased significantly, 9.4. 9.8 11.0 and 11.8 months (p=0.023). Examination of the entire population showed that the median overall survival of those not receiving chemotherapy was 3.51 months, whereas those receiving first-line therapy was 7.9 months and for those receiving second-line or beyond therapy the survival was 17 months (p<0.001).

The authors note that “The benefits of chemotherapy and specifically second-line treatment on patient outcomes are substantial, even in a widely mixed population of patients, which confirms the advances seen in clinical trial populations over the past decade“. Likewise, “As the options for treatment of NSCLC expand we anticipate that the outlook for lung cancer will continue to improve.”

Ho et al., (2014). Less Toxic Chemotherapy Improves Uptake of All Lines of Chemotherapy in Advanced Non–Small-Cell Lung Cancer: A 10-Year Retrospective Population-Based Review. J. Thoracic Oncol., 9: 1180-1186, doi: 10.1097/JTO.0000000000000225 [Abstract]

Prostate cancer in younger men — More frequent and aggressive?

Early onset prostate cancer is a newly identified, more aggressive subtype often linked to genetic mutations.

The number of younger men diagnosed with prostate cancer has increased nearly 6-fold in the last 20 years, and the disease is more likely to be aggressive in these younger men, according to a new analysis from researchers at the University of Michigan Comprehensive Cancer Center.

Typically, prostate cancer occurs more frequently as men age into their 70s or 80s. Many prostate cancers are slow-growing and many older men diagnosed with early stage prostate cancer will end up dying from causes other than prostate cancer.

But, the researchers found, when prostate cancer strikes at a younger age, it’s likely because the tumor is growing quickly. “Early onset prostate cancer tends to be aggressive, striking down men in the prime of their life. These fast-growing tumors in young men might be entirely missed by screening because the timeframe is short before they start to show clinical symptoms,” says Kathleen A. Cooney, M.D., professor of internal medicine and urology at the University of Michigan.

Peter Rich was 59 when he was diagnosed with stage 4 prostate cancer. His Prostate-Specific Antigen (PSA)  levels were relatively low, but the disease had already spread to his ribs, spine and lymph nodes.

To think of mortality was devastating. It was like any major loss – shock and numbness,” says Rich, who had to retire from his job as a school social worker because of his cancer treatment. Rich was diagnosed six years ago. Average survival for stage 4 disease is generally less than three years.”What we both said when we got the diagnosis was, well, that’s not acceptable,” Rich says of himself and his wife, Carol. “I’m a fighter.”

Cooney and Scott Tomlins, M.D., Ph.D., assistant professor of pathology at U-M, are leading a new study supported by the U.S. Department of Defense to look at DNA of both normal and cancerous prostate tissue of men diagnosed with advanced prostate cancer before age 61. They will be looking at whether these younger men are more likely to have inherited genetic mutations. For more information on this study, contact the U-M Cancer AnswerLine at 800-865-1125.

Men with a family history of prostate cancer have a two- to three-times greater chance of being diagnosed with prostate cancer. That risk increases for young men with multiple affected relatives. Prostate cancer runs in Rich’s family. Like Rich, his brother was diagnosed in his 50s, and a cousin and uncle had prostate cancer as well.

The new analysis, which appears in Nature Reviews: Urology, found that men with early onset prostate cancer had more genetic variants than men diagnosed with prostate cancer at a later age. The researchers suggest that genetic counseling or increased surveillance in younger men with a family history of prostate cancer may be warranted.

American men have a 16 percent risk of developing prostate cancer in their lifetime, but only a 3 percent lifetime risk of dying from it. The challenge, Cooney says, is understanding which subset of prostate cancers are most likely to be aggressive and deadly.

The unexpectedly poor prognosis of advanced stage early onset prostate cancer supports the idea that a new clinical subtype might exist in the subset of men with early onset prostate cancer. This subtype is more aggressive and requires more specialty expertise, including genetic sequencing,” Cooney says.

Salinas et al., (2014). Prostate cancer in young men: an important clinical entity. Nat. Rev. Urology11:317–323 doi:10.1038/nrurol.2014.91 [abstract]

Sunshine vitamin ups bowel cancer survival odds

Bowel cancer patients with high levels of vitamin D in their blood are more likely to survive the disease, a study shows.

Patients with the highest levels of vitamin D have half the risk of dying compared with those with the lowest levels, findings reveal. The study is the first to correlate total blood levels of vitamin D in bowel cancer patients after their diagnosis – which includes that produced after exposure to sunlight and that obtained from dietary sources – with their long term survival prospects.

The University of Edinburgh team tested blood samples from almost 1600 patients after surgery for bowel cancer. The greatest benefit of vitamin D was seen in patients with stage 2 disease, at which the tumour may be quite large but the cancer has not yet spread.Researchers found that three quarters of the patients with the highest vitamin D levels were still alive at the end of five years, compared with less than two thirds of those with the lowest levels.

The results show that vitamin D is associated with a much better chance of cancer survival, although the nature of this relationship is not clear from this study. The study’s authors aim to set up a clinical trial to test whether taking vitamin D tablets in combination with chemotherapy can improve bowel cancer survival rates. Measuring vitamin D levels in bowel cancer patients could also provide a useful indication of prognosis, the scientists say.

Professor Malcolm Dunlop, of the Medical Research Council Human Genetics Unit at the University of Edinburgh, said: “Our findings are promising but it is important to note that this is an observational study. We need carefully designed randomised clinical trials before we can confirm whether taking vitamin D supplements offers any survival benefit for bowel cancer patients.”

Zgaga et al., (2014). Plasma Vitamin D Concentration Influences Survival Outcome After a Diagnosis of Colorectal Cancer. J. Clin. Oncol., EPub Ahead of Print,  doi:10.1200/JCO.2013.54.5947 [Abstract]

Antibody halts cancer-related wasting condition

Study pinpoints a molecular cause of cachexia, and hints at a potential treatment

New research raises the prospect of more effective treatments for cachexia, a profound wasting of fat and muscle occurring in about half of all cancer patients, raising their risk of death, according to scientists from Dana-Farber Cancer Institute. Many strategies have been tried to reverse the condition, which may cause such frailty that patients can’t endure potentially life-saving treatments, but none have had great success.

Scientists reporting in the July 13 advanced online edition of Nature, led by Bruce Spiegelman, PhD, demonstrated that in mice bearing lung tumors, their symptoms of cachexia improved or were prevented when given an antibody that blocked the effects of a protein, PTHrP, secreted by the tumor cells. PTHrP stands for parathyroid hormone-related protein, and is known to be released from many types of cancer cells.

The scientists said their findings are the first to explain in detail how PTHrP from tumors switches on a thermogenic (heat-producing) process in fatty tissues, resulting in unhealthy weight loss. This tumor-derived protein, they found, stimulated “beige” or brown fat cells mixed with stored white fat in the body, causing the white fat to “brown” – that is, generate heat and cause weight loss even when the animals were at rest.

The researchers carried out two experiments using mice that developed lung tumors and cachexia. In one, they administered a polyclonal antibody that specifically neutralizes PTHrP and found that it prevented the wasting almost completely, while untreated animals became mildly cachexic. In a second experiment, the antibody treatment prevented the loss of muscle mass and improved muscle function, while control animals developed severe muscle-wasting.

You would have expected, based on our first experiments in cell culture, that blocking PTHrP in the mice would reduce browning of the fat,” said Spiegelman. “But we were surprised that it also affected the loss of muscle mass, and improved health.”

The research suggested that PTHrP alone doesn’t directly cause muscle wasting, yet blocking the protein’s activity prevents it.

 
Thus, the role of PTHrP “is definitely not the whole answer” to the riddle of cachexia, noted Spiegelman, but may be a necessary part, while other factors are also involved.

A collaborator on the study, Vickie E. Baracos, PhD, at the University of Alberta in Edmonton, Canada, provided the blood of 47 patients with lung or colon cancer who were cachexic. Serkan Kir, PhD, from the Spiegelman lab – and first author on the paper –found increased levels of PTHrP in 17 of the patients. Those patients had significantly lower lean body mass and were producing more heat energy at rest than were the other patients in the group.

It may turn out that the PTHrP mechanism is responsible for cachexia in a subset, but not all, cancer patients, Spiegelman suggested. Before trying the anti-PTHrP antibody in human patients, he said, “clinicians would probably first want to find out if the protein is elevated in certain cancers, and determine which patients would be good candidates for a clinical trial.”

Barrett Rollins, MD, PhD, Dana-Farber’s chief scientific officer, commented that the report from Spiegelman and his colleagues “provides a new roadmap for developing a rational, mechanistically based treatment for this incredibly debilitating condition that occurs in such a large number of our patients. Until now we’ve had no truly effective way to reverse this horrible complication.”

Patients with upper gastrointestinal and pancreatic cancers are the most likely to develop cachexia, and the condition affects about 80 percent of terminal cancer patients. Current strategy is to give appetite stimulants and nutrient supplements, along with medications to counteract some of the molecular pathways believed to underlie the wasting process, but with limited success.

Kir et al., (2014). Tumour-derived PTH-related protein triggers adipose tissue browning and cancer cachexia. Nature, EPub Ahead of Print, doi:10.1038/nature13528 [Abstract]

The Side Effects of Chemotherapy on the Body

Chemotherapy drugs are powerful enough to kill rapidly growing cancer cells, but they also can harm perfectly healthy cells, causing side effects throughout the body.

Cancer cells divide more quickly than healthy cells, and chemotherapy drugs effectively target those cells. Unfortunately, fast-growing cells that are healthy can be damaged too. There are many different chemotherapy drugs with the potential for many different side effects. These effects vary from person to person and from treatment to treatment.

Factors that play a role in side effects include other ongoing treatments, previous health issues, age, and lifestyle. Some patients experience few side effects while others feel quite ill. Although most side effects clear up shortly after treatment ends, some may continue well after chemotherapy has ended, and some may never go away.

Chemotherapy drugs are most likely to affect cells in the digestive tract, hair follicles, bone marrow, mouth, and reproductive system. However, cells in any part of the body may be damaged.

– See more at: http://www.healthline.com/health/cancer/effects-on-body#sthash.ZbSMeewY.dpuf