Cancer stem-like cells have been implicated in the genesis of a variety of malignant cancers. Research scientists at Cedars-Sinai Medical Center’s Maxine Dunitz Neurosurgical Institute have isolated stem-like cells in benign (pituitary) tumors and used these “mother” cells to generate new tumors in laboratory mice. Targeting the cells of origin is seen as a possible strategy in the fight against malignant and benign tumors.

Cells generated from the pituitary tumor cells had the same genetic makeup and characteristics as the original tumors and were capable of generating new tumors, according to an article in the July 2009 issue of the British Journal of Cancer, posted online June 30.

Normal stem cells have the ability to self-renew and the potential to “differentiate” into any of several types of cells. Tumor stem-like cells appear to have the same self-renewing and multipotent properties, but instead of producing healthy cells, they propagate tumor cells. In this study, benign tumor stem-like cells were analyzed for their genetic makeup and behavior.

Pituitary adenomas have unusual characteristics that provided significant clues about several types of stem cells. The pituitary gland, situated at the base of the brain behind the nose, is stimulated by hormones from the hypothalamus gland to produce a variety of hormones that control other glands throughout the body. About half of all pituitary adenomas - which arise from pituitary gland tissue - also have this hormone-producing capability.

In these studies, the scientists isolated stem-like cells from both hormone-producing and non-producing pituitary adenomas that had been surgically removed from eight patients. Laboratory experiments focused on tumor stem cells from one tumor that produced growth hormone and one tumor that produced no hormones. Both types of stem-like cells were found to be self-renewable and multipotent, meaning they expressed proteins that could enable their offspring to differentiate into several types of cells.

Studies also showed that both hormone-producing and non-producing tumor stem cells can be differentiated into hormone-producing cells, with the specific hormones produced being determined by the characteristics of the original pituitary tumor.

Consistent with the researchers’ earlier findings in cancer stem-like cells of malignant brain tumors, the tumor stem cells - but not the “daughter” cells - appeared to be resistant to chemotherapy. This suggests that even if most of a tumor’s cells can be killed, stem-like cells may survive and regenerate the tumor.

When tumor stem-like cells were implanted into laboratory mice, they generated new tumors that had the same genetic composition and characteristics as the original tumors. Cells from the new tumors, later transplanted into other mice, maintained the same tumor-specific properties.

“Although previous studies have offered evidence of the existence of stem-like cells in pituitary adenomas, in this study we scrutinized these cells for composition and function, demonstrating that stem-like cells exist in benign tumors,” said neurosurgeon John S. Yu, M.D., director of Surgical Neuro-oncology at Cedars-Sinai Medical Center. He is senior author of the journal article.

Although pituitary adenomas are typically noncancerous, they can cause significant injury or illness, either by compressing important structures, such as the optic nerve, or by creating hormone imbalances that can have wide-ranging and serious consequences. Identifying the mechanisms that enable these and other tumors to form may provide unique targets for new, more effective therapies.

“From our work with cancer stem-like cells in malignant brain cancers, it appears that stem cells from different cancers - or possibly even within the same tumor - may use different signaling pathways and have different implications for disease progression and prognosis. Findings from the pituitary tumor study generally support the cancer stem cell hypothesis, suggesting that similar mechanisms may be involved in the generation of both malignant and benign tumors,” said Keith L. Black, M.D., chairman of the Department of Neurosurgery at Cedars-Sinai.

“Confirmation of the existence of stem-like cells in benign tumors is intriguing,” said Yu, “but many questions remain to be answered, particularly in defining the molecular mechanisms involved. We need to find out if there is any relationship between tumor stem cells and normal pituitary stem cells, and how stem cells from benign tumors are different from and similar to those of malignant tumors.”

Research scientists from Cedars-Sinai’s departments of Neurosurgery, Pathology and Laboratory Medicine, and Surgery participated in these studies, which were partly funded by the National Institutes of Health (NIH) and the Italian Association for Neurological Research (ARIN).

Citation:
“Isolation of tumour stem-like cells from benign tumours.” July 2009:
http://www.nature.com/bjc/journal/v101/n2/abs/6605142a.html
British Journal of Cancer

Source
Cedars-Sinai Medical Center

SRI International, an independent nonprofit research and development organization, has announced that SRI’s Center for Cancer Research was selected by the National Cancer Institute (NCI) for a leading role in the newly-formed “Chemical Biology Consortium” (CBC), a collaborative drug discovery partnership focused on advancing new cancer therapeutics active against novel molecular and genetic cancer targets. Based on its track record of cancer drug discovery and development, SRI was chosen to lead three of the CBC’s research and development centers: Comprehensive Chemical Biology Screening, Chemical Diversity, and Specialized Applications.

SRI has decades of experience in successfully identifying, developing and advancing novel compounds into clinical evaluation. SRI’s Center for Cancer Research, comprised of biologists and medicinal chemists with expertise in fundamental and applied cancer research, focuses on the study of tumor microenvironment, tumor metabolism, and aberrant signaling pathways that cause cancer. Through collaborative partnerships, SRI’s Center for Cancer Research has been successful in generating an extensive drug pipeline translating discoveries into beneficial treatments. SRI’s drug discovery process, guided by a combination of biological screens and computational methods, will be a key component of the NCI Chemical Biology Consortium program.

“SRI is proud to be selected to join this innovative NCI program and to continue our long-standing support of NCI’s mission to discover, develop, and bring new drugs to cancer patients,” said Lidia Sambucetti, Ph.D., senior director of SRI’s Center for Cancer Research. “Our multidisciplinary research team will bring proven expertise in fundamental and applied cancer research, backed by SRI’s fully-integrated preclinical capabilities.”

The goal of the Chemical Biology Consortium is to discover and develop new cancer therapeutics, particularly those that are beyond the scope of standard biopharmaceutical practice. The CBC will focus on therapeutic opportunities in high-risk, under-represented areas to advance the discovery of compounds active against novel molecular and genetic cancer targets.

Sambucetti will serve as the overall principal investigator of SRI’s CBC program and the Comprehensive Chemical Biology Screening Center. She will collaborate with Mary Tanga, Ph.D., an SRI senior director of medicinal chemistry, who will lead the Chemical Diversity Center, and Keith Laderoute, Ph.D., an SRI distinguished scientist, who will lead the Specialized Applications Center.

As the principal investigator of the Comprehensive Chemical Biology Screening Center, Sambucetti was invited to join the CBC Steering Committee, an NCI advisory panel that will work to ensure that CBC Centers are efficiently bridging the gap between basic scientific findings and NCI-supported clinical research.

To optimize high-quality leads and accelerate the drug discovery process, SRI will be working with BioComputing Group, Inc., a developer of computational screening, hit-to-lead, and lead optimization tools with particular emphasis on structure-guided drug discovery. These tools employ novel molecular descriptors that are derived from active compounds within the target family and from the structure of the target protein that can be applied to the evaluation of compounds from a library as well as compounds not yet synthesized. BioComputing Group, Inc. (www.BioPredict.com) has a significant track record of success in applying its tools in a hypothesis-driven paradigm to accelerate drug discovery efforts of its collaborators and clients, having placed multiple compounds into clinic with significantly reduced numbers of compounds screened and synthesized and with significantly shortened time frames.

This project has been funded in whole or in part with Federal Funds from the National Cancer Institute, National Institutes of Health, under Contract No. N01-C0-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does the mention of trade names, commercial products or organizations imply endorsement by the U.S. Government.

Source:
Dina Basin

SRI International

The National Institute for Health and Clinical Excellence (NICE) today issued its recommendation for the use of MabThera® (rituximab) in the UK’s most common form of leukaemia, chronic lymphocytic leukaemia (CLL).1,2,3 NICE’s final guidance recommends rituximab in combination with fludarabine and cyclophosphamide (FC) chemotherapy as an option for previously untreated patients with CLL.4 The addition of rituximab to FC chemotherapy has been proven to halt progression of the disease by 10.5 months longer than chemotherapy alone, and more than doubles the number of CLL patients achieving complete remission, compared to chemotherapy.5,6 More than 20,000 people in the UK are living with CLL and there are an estimated 3,700 new cases every year.7,8 Professor John Gribben, Consultant Haematologist and Medical Oncologist, Barts and The London NHS Trust, commented:

“The ability to add rituximab to chemotherapy is a major advance in the way we can treat chronic lymphocytic leukaemia. Where previously our goal was just to improve symptoms, for the first time we now have a treatment combination that is capable of producing much higher remission rates and more durable responses. This is great news for patients and clinicians, who have been waiting many years for an advance that provides significant benefits compared to chemotherapy alone.”

In the pivotal clinical trial, the addition of rituximab to FC chemotherapy extended the period of time after treatment in which the disease progression is halted (’progression-free survival’) by 10.5 months
when compared to chemotherapy alone (3.5 years vs. 2.7 years).6 In addition, the number of patients achieving complete remission was more than twice that of chemotherapy alone (36 per cent vs. 17 per
cent).5

Tony Gavin, Director of Campaigning and Advocacy, Leukaemia CARE, said: “This NICE recommendation means many more people with the most common form of leukaemia should be able to Roche Products Limited
access rituximab on the NHS. Now Final Guidance is granted, rituximab should be made available immediately to all patients eligible for this treatment.”

Jane Barnard, Chair of the CLL Support Association, said: “This is great news for CLL patients, many more of whom will now have the potential to gain additional time in remission and relief from debilitating symptoms such as extreme fatigue and the pain and discomfort of swollen glands.”

CLL is a blood cancer caused when abnormal white blood cells (B-cells) grow out of control. They then outnumber healthy cells in the bone marrow and prevent the immune system from working normally. CLL accounts for approximately one third of leukaemias.2

“Roche welcomes this NICE recommendation for MabThera. CLL is a devastating disease that has no cure. Longer, deeper remissions allow people to return to work and family life with reduced or eliminated symptoms,” said John Melville, General Manager, Roche Products Ltd.

Adding rituximab to chemotherapy in CLL results in an overall manageable tolerability profile, which helps maintain patients’ quality of life. In the pivotal trial, adding rituximab to FC led to a higher incidence of haematological toxicity (where the bone marrow is suppressed, making it harder for the body to produce blood cells). Specifically, the increased incidence of neutropenia (a reduction in a specific type of white blood cell) was statistically significant, but this did not lead to a significant difference in infections between the two types of treatment.5

Please refer to the rituximab Summary of Product Characteristics for full details, available at:
http://www.emc.medicines.org.uk.

About CLL

Chronic lymphocytic leukaemia (CLL) is a blood cancer caused by a type of abnormal white blood cell (B-cells). Healthy B-cells are involved in fighting infection by producing antibodies. CLL leads to the suppression of the immune system, failure of the bone marrow and infiltration of malignant cells into organs. CLL can spread to the lymph nodes, spleen, liver, central nervous system and other organs. It does not usually form a solid mass or tumour.2 Further information in the CLL backgrounder
(COMM00333a).

About Rituximab (MabThera)

Rituximab is a monoclonal antibody (sometimes shortened to ‘MAB’), a type of man-made molecule that targets specific cells, or parts of cells, for destruction. Rituximab binds to a particular protein, the CD20 antigen, which is expressed on the surface of normal and malignant mature B-cells, a type of white blood cell vital to the body’s immune system. Disruption to the normal function of B-cells is a hallmark of many diseases, including non-Hodgkin lymphoma, rheumatoid arthritis and CLL. The way in which rituximab targets B-cells means it is capable of tackling more than one disease. Rituximab is licensed in chronic lymphocytic leukaemia, certain types of non-Hodgkin lymphoma and rheumatoid arthritis.

CLL8 Trial

CLL8, the pivotal trial on which rituximab’s first-line CLL licence is based, was an international, multicentre study. It included 817 patients with CLL who needed treatment for the first time. The study was conducted at 191 study sites across 11 countries. The trial was designed to evaluate the efficacy and tolerability of rituximab plus chemotherapy versus chemotherapy alone for initial treatment. The primary endpoint of the study was progression-free survival.

References

1. CLL Support Association: http://www.cllsupport.org.uk/aboutcll.htm Accessed 1 July 2009

2. Cancer Research UK: http://www.cancerhelp.org.uk/help/default.asp?page=17964Accessed 1 July 2009

3. Byrd JC et al. ‘Randomized phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic,
untreated patients with B-cell chronic lymphocytic leukemia: results from Cancer and Leukemia Group B 9712 (CALGB 9712)’, Blood 2003;
101: 6-14

4. National Institute for Health and Clinical Excellence. Single Technology Appraisal TA174, July 2009: Rituximab for the first-line treatment of
chronic lymphocytic leukaemia. http://www.nice.org.uk/TA174.

5. Rituximab (MabThera®) Summary of Product Characteristics, March 2009

6. Hallek H. ASH presentation, December 2008. Data on file. MAB015

7. The estimated 20-year prevalence of CLL in the UK is 20,185. Figure has been calculated by applying the 2005 Scottish prevalence rates
(http://www.isdscotland.org/isd/183.html) per 100,000 to the 2005 UK population. Accessed 1 July

Source
Roche