A rare case of a mother and her infant developing the exact same cancer has allowed an international team of researchers to solve a puzzle that has perplexed scientists and clinicians for a century.

Scientists at The Institute of Cancer Research (ICR) and colleagues in Japan, with funding from Leukaemia Research, investigated a situation in which leukaemic cells appeared to have defied accepted theories of biology and spread through the womb from a Japanese woman to her daughter.

Around 30 previously known cases of a mother and infant appearing to share the same cancer, usually leukaemia or melanoma, had already raised suspicions that such spread was possible. But there was no genetic evidence to support this theory, and scientists did not know how it could happen as the baby’s immune system should have recognised and destroyed any invasive cancer cells that were of maternal - and therefore ‘foreign’- origin.

In a study published in Proceedings of the National Academy of Sciences today, the ICR scientists used advanced genetic fingerprinting to prove for the first time that the infant’s leukaemic cells were unquestionably of maternal origin.

They found both patients’ leukaemic cells carried the identical mutated cancer gene (called BCR-ABL1), but the infant had not inherited this gene. This meant the child could not have developed this type of leukaemia in isolation.

To investigate how the cells could have crossed the placental barrier and survived in the offspring, the scientists looked for evidence of some form of immunological acceptance or tolerance of the foreign cells by the foetus.

They examined the genes of the cancer cells in the infant and found a deletion mutation - some DNA missing in the region that controls expression of the major histocompatibility locus (HLA). This was significant because HLA molecules primarily distinguish one individual, and his or her cells, from another, so the absence of these molecules on the cancer cells meant the infant’s immune system would not have recognised that they were foreign.

Professor Mel Greaves, who led the study at the ICR, says: “It appears that in this and, we presume, other cases of mother to offspring cancer, the maternal cancer cells did cross the placenta into the developing foetus and succeeded in implanting because they were invisible to the immune system.

“We are pleased to have resolved this longstanding puzzle. But we stress that such mother to offspring transfer of cancer is exceedingly rare and the chances of any pregnant woman with cancer passing it on to her child are remote.”

Dr David Grant, Scientific Director at Leukaemia Research, said: “The important message from this fascinating piece of research is that leukaemia cells can be destroyed by the immune system. Harnessing the power of the immune system to first cure and then protect patients from leukaemia is one of our priority areas of research.”

The study was funded by Leukaemia Research, the Kay Kendall Leukaemia Fund and the ICR.

Notes

The study will be published on online on 12 October in the journal Proceedings of the National Academy of Sciences under the title: ‘Immunologically silent cancer clone transmission from mother to offspring’. Corresponding author: Professor Mel Greaves, Section of Haemato-Oncology, The Institute of Cancer Research, Brookes Lawley Building, 15 Cotswold Road, Sutton, Surrey SM2 5NG, United Kingdom.

Leukaemia Research

Leukaemia Research is the only national charity devoted exclusively to improving treatments, finding cures and learning how to prevent leukaemia, Hodgkin’s and other lymphomas, myeloma and the other related blood disorders, diagnosed in 24,500 people in the UK every year. Further information, including patient information booklets, is available from http://www.lrf.org.uk or call 020 7405 0101.

Source
Institute of Cancer Research

Scientists have identified an enzyme that is crucial for turning abnormal but non-malignant breast tissue into tumours, according to a study published today in Cell online.

Blocking the enzyme lysyl oxidase (LOX) reduced the chance a tumour would form, and also meant tumours that did develop were smaller and less aggressive.

“Our study shows that stiffening of the breast tissue controlled by enzymes such as LOX are a key factor in Dr Janine Erler from The Institute of Cancer Research in the UK says. “The enzyme triggers a clear physical change in breast tissue and, if we could stop this happening, we expect it would slow the growth of any cancers that did develop and make them easier to eradicate.”

The supportive tissue surrounding cancer cells is shaped differently to healthy tissue as well as stiffer and more fibrous. These properties help doctors detect breast cancers, but until now scientists have not known what was causing these modifications.

In the latest study, the team found LOX caused the structure of collagen, the major component of the supportive tissue, to change in a process known as cross-linking. In experimental models, higher levels of LOX increased the levels of collagen in mammary glands, made the tissue stiffer and correlated with a higher frequency of tumours invading the breast tissue.

When the team used chemicals or an antibody to block LOX, they found collagen in the mammary glands contained fewer cross-links and the tissue was less fibrous. Most importantly, they found fewer and smaller tumours had formed in breast tissue and the tumours that did form were of a lower grade (less aggressive).

Dr Erler’s previous studies have already highlighted the importance of LOX in cancer spread, showing that it promotes metastasis by sending out signals that prepare a new area of the body for invasion. The new study shows that LOX is also crucial for primary tumour progression.

Although the tests were carried out in breast cancer, Dr Erler says it is likely a similar mechanism occurs in other cancer types as LOX levels are known to be elevated in many cancer types. Until recently, however, most investigators have focused only on the tumour cells themselves. What makes the current study so unique is that the investigators showed that it is the cells within the connective tissue surrounding the growing tumours that express the LOX enzyme. These cells induce the tissue stiffening and fibrosis that then, through mechanical forces, promote the tumour cells to become invasive. These observations are significant because they emphasize the need to treat tumours early and to focus on the tissue microenvironment - not just the tumour but the surrounding area too.

The findings also suggest that cross-linking and stiffness in supporting tissue in general is important in tumour progression, and imply that other enzymes and molecules that support this process could also promote cancer formation.

“This study may also help explain why the rate of breast cancer increases dramatically with age - aged tissues are stiffer and contain higher levels of abnormal collagen cross-links,” study co-author Professor Valerie Weaver from the University of California, San Francisco, says. “I’m cautiously optimistic. We still have a lot more work to do, but this is certainly exciting.”

Further testing established other factors that could be acting in combination with LOX, including cancer genes such as ErbB2 and other molecules including PI3kinase. Professor Weaver says the study shows that cancer is best viewed as a complex process of changes in tissue remodelling that is tightly controlled by many biochemical and mechanical factors.

Scientists from the University of Pennsylvania, University of California, San Francisco, Stanford University School of Medicine, University of Hawaii at Manoa and the University of North Carolina also contributed to this study.

Source
The Institute of Cancer Research (ICR)

When cells experience DNA damage, they’ll try to repair it. But if that fails, the damaged cells are supposed to self-destruct, a process called apoptosis. A cancer researcher at Robarts Research Institute at The University of Western Ontario has identified a protein that regulates apoptosis, a new discovery which has implications for both the diagnosis and treatment of cancer. Caroline Schild-Poulter’s findings are now published online in the journal Molecular Cancer Research.

“The protein we’ve identified, RanBPM, is directly involved in activating apoptosis,” explains Schild-Poulter who is also an assistant professor in the Department of Biochemistry at Western’s Schulich School of Medicine & Dentistry. “One of the hallmarks of cancer is that the cells don’t initiate apoptosis despite having defects in their genetic material. In other words the damaged cells do not commit suicide, and this develops into cancer. Failure to activate apoptosis also makes it difficult to cure cancer. You cannot kill these cells by causing DNA damage to them using chemotherapy or radiation, because these cells resist dying.”

While more research is needed to fully understand how this protein functions, Schild-Poulter believes RanBPM could be targeted to re-activate apoptosis, killing cancer cells. The protein may also be a marker used to predict whether a tumour will go on to become malignant.

Schild-Poulter holds the position of “Fuller Scientist” at Robarts Research. Her research is funded through a donation from Marilynne Fuller, whose husband Robert died of cancer in 2002.

Source: Kathy Wallis

University of Western Ontario

Philanthropists Irwin and Joan Jacobs of La Jolla, CA are giving a $6.5 million gift to UCSF for head and neck cancer research. It is believed to be the largest private, U.S. gift for research supporting this disease.

Irwin Jacobs is the founder, retired CEO, and current board member of telecommunications giant Qualcomm. He is also a survivor of a rare form of the cancer.

The gift will establish two distinguished professorships at UCSF for head and neck cancer research, one in the Department of Otolaryngology-Head and Neck Surgery and one in the Department of Radiation Oncology:

• The Irwin Mark Jacobs and Joan Klein Jacobs Distinguished Professorship in Head and Neck Cancer - In honor of David W. Eisele, MD, professor and chair of otolaryngology-head and neck surgery, who is the first recipient.

• The Irwin Mark Jacobs and Joan Klein Jacobs Distinguished Professorship in Head and Neck Cancer Radiation Oncology - In honor of Jeanne Quivey, MD, professor of clinical radiation oncology, who is the first recipient.

The gift was announced by UCSF Chancellor Susan Desmond-Hellmann, MD, MPH, at a special celebration ceremony attended by the Jacobses and other special guests.

In 2007, Jacobs discovered, while showering in his La Jolla home, a bump at the back of his jaw near his left ear. Initially, he consulted a dentist, believing it was a dental problem. The bump was later diagnosed as an adenoid cystic carcinoma, a cancer that generally originates in the salivary glands and for Jacobs occurred in his parotid gland.

Within weeks of his diagnosis, Jacobs was under the care of Eisele, who removed the tumor with a parotidectomy, preserving Jacobs’ facial nerve. Quivey oversaw Jacobs’ postoperative radiation therapy.

Jacobs recounted that Quivey “warned me I’d probably lose all my hearing in the left ear, which I haven’t.” He added, “It did take away my sense of taste for a while. There was a time when the only thing that tasted good was vanilla ice cream.”

Head and neck cancers account for about three to five percent of all cancers in the U.S., according to the National Cancer Institute, with a small proportion of those cancers occurring in the salivary glands.

“It’s an unusual tumor,” said Eisele. “We don’t understand very well why these tumors occur. We don’t understand the variability from patient to patient. We’re very interested in the molecular underpinnings and the behaviors of these tumors so we can come up with more effective therapeutic strategies. The Jacobs’ generosity will help us hopefully make some creative discoveries.”

In addition to their department positions, both Eisele and Quivey are affiliated with the UCSF Helen Diller Family Comprehensive Cancer Center.

Source:
Elizabeth Fernandez

University of California - San Francisco

Wei Zheng, M.D., Ph.D., M.P.H., cancer epidemiologist with Vanderbilt-Ingram Cancer Center, Nashville, Tenn., has received a prestigious MERIT Award from the National Institutes of Health (NIH) for his research on women and cancer. The MERIT (Method to Extend Research in Time) awards provide long-term support to investigators with impressive records of scientific achievement in research areas of special importance or promise. Fewer than five percent of NIH-funded investigators are selected to receive MERIT awards, which provide financial support for up to 10 years without competitive review.

“I am very excited to receive this award and the award is recognition of the teamwork involved in our research,” said Zheng, Ingram Professor of Cancer Research and director of the Vanderbilt Epidemiology Center. “Epidemiological studies require a multidisciplinary team and I am privileged to work with so many talented, dedicated people at Vanderbilt and many other institutions.”

The MERIT award will support continuation of the Shanghai Women’s Health Study, a population-based study of 75,000 women who were recruited between 1997 and 2000 with a major focus to identify associations between diet and lifestyle and diseases such as cancer.

Zheng and his team are studying the impact of soy foods, tea, ginseng and cruciferous vegetables on cancer risk and health. In addition to answering detailed surveys, the women provide blood and urine samples for identification of exposure to dietary influences as well as potential disease biomarkers.

“Many studies have looked at diet and lifestyle factors that are bad for individuals but we are trying to find things that are protective against disease,” said Zheng. “These observational studies may allow us to gather enough evidence to launch a large trial that tests the effects of some of these compounds.”

Zheng and his investigative team also are conducting genome-wide association studies, scanning the entire genome for disease susceptibility biomarkers. They are studying telomeres, DNA copy number variations, prostaglandin metabolites and other biomarkers that may be important in cancer and other disease processes.

“Wei Zheng is an outstanding cancer investigator and mentor to many of our young researchers,” said Bill Blot, Ph.D., associate director of Cancer Prevention, Control and Population-Based Research at Vanderbilt-Ingram. “The MERIT award recognizes the importance of this high-impact research on international health.”

Zheng said the award also validates the contributions of the thousands of women in the study who donate their time as well as biological samples to provide answers to important health questions. He hopes this and other related studies will have a major impact on cancer and disease prevention.

“One of our goals is to build a risk assessment model for breast cancer that will allow us to identify those women at high risk for the disease for cost-effective prevention,” Zheng said.

Source
The Vanderbilt-Ingram Cancer Center

Critical Outcome Technologies Inc. (TSX VENTURE:COT), announced positive results today from combination agent animal experiments carried out at a prominent American cancer research facility. The results provide strong supportive evidence for the continued evaluation of COTI-2 in combination with conventional single agent therapy for the treatment of ovarian cancer:

- Tumor growth inhibition was significantly greater in the COTI-2 plus Doxil treated animals compared to the Doxil control group treated animals with:

– 12.5 mg/kg COTI-2 + 2 mg/kg Doxil causing 57% tumor growth inhibition

– 25 mg/kg COTI-2 + 2 mg/kg Doxil causing 54% tumor growth inhibition

– 2mg/kg Doxil control causing 29% tumor growth inhibition

- The effectiveness of the combination treatments with COTI-2 was apparent early in the study (day 4) and increased throughout the remainder of the study.

- Combination treatments were well tolerated.

“We are delighted to see that intravenous COTI-2 in combination with Doxil showed superior treatment results compared to Doxil alone as measured by significant tumor growth inhibition in an animal model of an aggressive human ovarian cancer (A2780). These results are significant because they add to the impressive data set of COTI-2, showing effectiveness, particularly in combination with first and second line agents, against multiple cancers and low toxicity,” said Dr. Wayne Danter, President and Chief Scientific Officer of Critical Outcome Technologies Inc. (COTI).

“COTI will share this new data with parties who have expressed interest in a commercial partnership related to COTI-2,” said Mr. Michael Cloutier, Chief Executive Officer of COTI.

The Company intends to repeat this study using an oral formulation of COTI-2 to compare the effectiveness of oral COTI-2 in an animal model of human disease.

The Company is also advising of a correction to its June 10, 2009 press release, which announced a brokered private placement as this should have read a non-brokered private placement.

Source
Critical Outcome Technologies Inc. (COTI)

View drug information on Doxil.