New strategy to attack tumor-feeding blood vessels

ScienceDaily (June 6, 2011) — Scientists at the Walter and Eliza Hall Institute have discovered a key molecule needed to kill the blood vessels that supply tumours.

See Also:Health & MedicineLung CancerCancerBreast CancerBrain TumorOvarian CancerLeukemiaReferenceMetastasisInterventional radiologyTumorLymphoma

The research team from the institute's Molecular Genetics of Cancer and Cancer and Haematology divisions found that for anti-cancer therapies that target tumour blood vessels to work the death- inducing molecule Bim is required. The finding could lead to improved anti-cancer treatments that are based on a two- or three-pronged attack on both the tumour and its blood supply. The research will be published online in the Journal of Experimental Medicine.

The growth of solid tumours, such as lung cancer, breast cancer and melanoma, depends on nutrients and oxygen being provided by the tumour blood supply. Cancer cells encourage the growth of blood vessels to feed a tumour by producing the hormone-like protein, vascular endothelial growth factor (VEGF). The research by Drs Edwina Naik, Leigh Coultas and Lorraine O'Reilly, and Professors Jerry Adams and Andreas Strasser showed that VEGF produced by tumours blocks production of Bim in the cells that line the tumour blood vessels.

New 'anti-angiogenic' medications that attack the blood vessels within tumours are showing promise in starving many types of cancers by reducing their blood supply.

In this study, in experimental melanoma, lung cancer and breast cancer models, Bim levels increased in the cells lining the blood vessels when VEGF was depleted by anti-angiogenic drugs, ultimately killing the blood vessel cells. VEGF depletion reduced the number of blood vessels in tumours, making the tumours shrink. However, in mice in which the blood vessels do not express Bim, VEGF depletion did not affect the number of tumour-associated blood vessels, and tumours grown in Bim-deficient mice did not respond to anti-angiogenic treatments.

Dr Strasser said this finding suggests that strategies for treating tumours by attacking the tumour blood supply could be optimised by incorporating drugs called BH3-mimetics that cause cell death by acting like Bim at a molecular level. "Similarly, therapies that increase the amount of Bim in tumour blood vessels could enhance the effects of anti-angiogenic agents," Dr Strasser said.

"BH3 mimetics may have two beneficial effects in cancer therapy. Our previous research had showed they can directly trigger death in tumour cells, particularly when the tumour is also attacked by chemotherapeutic drugs. We now think BH3-mimetics could also impact tumour cells indirectly by killing endothelial cells within tumours.

"This suggests that a promising new approach to the therapy of solid tumours may be to use a three-medication combination of a drug that specifically targets the tumour cell, an anti- angiogenic agent to impair the tumour blood vessels, plus a BH3 mimetic that will help the anti- tumour drug to directly kill the tumour cells and also will help the anti-angiogenic agent to kill the intra-tumoral endothelial cells, which in turn will starve the tumour, causing even more tumour cell death."

The research was supported by the Cancer Council Victoria, the National Health and Medical Research Council, the Australian Research Council, the US National Institutes of Health, the Leukemia and Lymphoma Society and Genentech.

Email or share this story:

Blood clotting and bowel cancer risk

ScienceDaily (June 6, 2011) — Back in the mid 19th century, a French doctor, Armand Trousseau, discovered a connection between cancer and thrombosis -- the formation of often dangerous blood clots that can lead to venous occlusion. Today it is known that cancer and its treatment change blood flow properties and thus promote the formation of clots. However, clots do not only occur as a side effect and consequence of cancer, but, vice versa, an increased blood clotting tendency may also be associated with an elevated cancer risk.

See Also:Health & MedicineBlood ClotsColon CancerBreast CancerLeukemiaCancerLung CancerReferenceHaemophiliaHormone replacement therapyHealth benefits of teaLeukemia

About twelve different blood proteins called clotting factors interact in a coordinated manner in the blood clotting (coagulation) process. In the same way as hemophilia (decreased blood clotting) is inherited, genes also play a role in an increased clotting tendency (thrombophilia): There are well studied gene variants (polymorphisms) of a number of clotting factors which are associated with an increased or decreased clotting tendency. Between two and five percent of the population carry such genetic variants.

At the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) in Heidelberg, scientists headed by Professor Dr. Hermann Brenner have been studying six gene variants of different clotting factors for a possible connection with colorectal cancer risk. In a large study, they analyzed the occurrence of these six variants in approximately 1.800 colorectal cancer patients and in the same number of healthy control persons.

The team found the most obvious connection for a variant that substantially increases the risk of thrombosis and which is known as factor V Leiden (FVL). Study participants who carry this genetic variant on both copies of their chromosome 1 were found to have a six fold increase in colorectal cancer risk compared to participants who carry two copies of the "standard variant" of factor V. If only one copy of chromosome 1 had the FVL variant, bowel cancer risk was not elevated.

Another connection with bowel cancer prevalence was found by the research team for a particular gene variant of clotting factor XIII: People with this mutation are slightly more rarely affected by venous thrombosis than those who carry the factor XIII standard version. Now the DKFZ team has shown that their colorectal cancer risk is also 15 percent lower. For the other four gene variants studied the team found no connection with bowel cancer risk.

It is known today that coagulation and carcinogenesis are associated. Thus, the interplay of all coagulation (clotting) factors leads to the formation of active thrombin, which, in turn, activates hemostatic fibrin. However, thrombin also contributes to the formation of new blood vessels and is able to dissolve the extracellular matrix, which is the adhesive that keeps cells together. Thrombin may thus make it easier for cancer cells to invade surrounding tissue.

"It is interesting that not every gene variant that increases the tendency to clot automatically also increases the risk of developing colorectal cancer. It also makes a difference whether the gene variant is present on both chromosomes or just on one of them. We therefore have to analyze in detail which clotting factors affect cancer risk and in what manner," explained study head Hermann Brenner. The knowledge of these connections is the first prerequisite for finding out whether and for whom drugs that affect blood clotting may prevent bowel cancer.

Email or share this story:

New therapy for blood cancers using drug combo

ScienceDaily (June 3, 2011) — Reported in the journal Clinical Cancer Research, the study determined the maximum tolerated dose with acceptable side effects for this novel drug combination. The trial represented the first time a proteasome inhibitor such as Bortezomib was combined with a cell cycle inhibitor such as Alvocidib to treat patients with cancer. Proteasome inhibitors work by blocking the action of proteasomes, which are large protein complexes that help destroy proteins that are no longer needed by the cell. Cell cycle inhibitors disrupt the sequence of events that allow cells to undergo cell division and duplication. They also have the ability to block gene transcription.

See Also:Health & MedicineLymphomaPersonalized MedicineLung CancerBreast CancerDiseases and ConditionsCancerReferenceClinical trialCOX-2 inhibitorChemotherapyTransplant rejection

The trial included 16 patients who had either indolent (non-aggressive) non-Hodgkin's lymphoma, mantle cell lymphoma or multiple myeloma. After they received the treatments over a 21-day cycle, there were two complete responses, meaning that all detectable traces of the cancer were gone, and five partial responses.

"Therapeutic responses tend to be rare in Phase I trials, but 44 percent of our patient sample responded to the therapy. Interestingly, some patients who previously had no response to Bortezomib, or progressed after Bortezomib therapy, responded to the combination," says Beata Holkova, M.D., a hematologist-oncologist at VCU Massey and co-investigator on this clinical trial. "Because of the small patient sample size, we can't draw definitive conclusions about the effectiveness of the therapy, but we were quite encouraged by the results."

The patients received Bortezomib intravenously on days 1, 4, 8 and 11 and Alvocidib on days 1 and 8. Bortezomib's therapeutic dose alone was not tested because it has already been established and approved to treat certain blood cancers. However, for Alvocidib, the researchers escalated the dose until the maximum tolerated dose was identified. The same researchers are also currently completing a second Phase I clinical trial testing a different delivery schedule of Alvocidib. Although not yet completed, the initial results of this trial appear comparable to the present study.

"This is one of the first trials of its type in which two targeted agents which interfere with two very different biological processes are being combined to treat patients with blood cancers," says co-investigator Steven Grant, M.D., associate director for translational research, co-program leader of Developmental Therapeutics and professor of internal medicine at VCU Massey.

The rationale for this study was developed in Grant's laboratory when synergistic interactions between proteasome and cell cycle inhibitors in malignant blood cancer cells were discovered by Yun Dai, M.D., Ph.D., associate professor of internal medicine at VCU Massey. This laboratory research established the basis for a V Foundation Translational Research Award, which with additional funding from the National Institutes of Health provided the resources necessary to translate the laboratory findings into clinical trials.

Moving forward, the researchers are working with the NCI to develop a Phase II clinical trial to test the effectiveness of this drug therapy. The trial will be conducted in collaboration with multiple institutions to compare the effectiveness of fixed doses of the drug combination in a larger patient population.

Grant and Holkova collaborated with John Roberts, M.D., E. Brent Perkins, M.D., Viswanathan Ramakrishnan, Ph.D., Mary Beth Tombes, R.N., M.N., Ellen Shrader, R.N., Martha Wellons, R.N., Kevin Hogan, Ph.D., Sarah Kolla, M.D., and Talreja, Neha, all from VCU Massey Cancer Center and the VCU School of Medicine; G. David Roodman, M.D., Ph.D., from the University of Pittsburgh Department of Medicine; Domenico Coppola, M.D., Loveleen Kang, Jana Dawson and Daniel Sullivan, M.D., from H. Lee Moffitt Cancer Center and Research Institute; Robert K. Stuart, M.D., from the University of South Carolina Department of Medicine; and William D. Figg, Sr., Pharm.D., Austin Doyle, M.D., and John Wright, M.D., Ph.D., from the National Cancer Institute.

Email or share this story:

Study reveals origins of a cancer affecting the blood and bone marrow

ScienceDaily (May 16, 2011) — A new study by the NYU Cancer Institute, an NCI-designated cancer center, sheds light on the origins of myeloid leukemia, a type of blood cancer that affects children and adults. The researchers discovered that novel mutations in an intracellular communication pathway called Notch led to the cancer, pointing to a potential new target for treating this disease. Notch has already been implicated in another type of blood cancer called T-cell acute lymphoblastic leukemia, but the new research found an unexpected role for it in myeloid leukemia.

See Also:Health & MedicineLeukemiaLung CancerBrain TumorLymphomaCancerStem CellsReferenceLeukemiaNatural killer cellBone marrowLymphoma

The study is published in the May 12, 2011 issue of the journal Nature.

"This study shows the power of the Notch signaling pathway in myeloid leukemias," says Iannis Aifantis, PhD, associate professor in the Department of Pathology at NYU Langone Medical Center and a member of the NYU Cancer Institute, who led the new study. "This discovery," he says, "suggests a potential for future targeted therapies." Dr. Aifantis is also a Howard Hughes Medical Institute Early Career Scientist.

Last year, acute myeloid leukemia was diagnosed in more than 12,000 adults and the disease claimed nearly 9,000 lives in the United States, according to the National Cancer Institute. The blood cancer is the most common type of acute leukemia in adults. Normally, the bone marrow makes blood stem cells (immature) that mature over time. Some of these are a form called myeloid and others are lymphoid. The lymphoid stem cell develops into a white blood cell, while the more-versatile myeloid stem cell develops into red blood cells, white blood cells, and platelets, which prevent clotting. Cancer occurs when too many immature myeloid stem cells are produced in the blood and bone marrow.

The Notch signaling pathway, the complex web of intracellular interactions that occurs after a protein called Notch is activated on the cell's surface, is a well known actor in cancer, but the new study reveals that the varied members of this pathway function in unexpected ways to produce disease. Notch is named for a particular kind of mutation, first identified almost 100 years ago, that gives fruit flies notched wings.

The study evaluated mutations in the Notch pathway in mice models of the disease, and also in blood samples from patients with chronic myeloid leukemia. Researchers identified several mutations that inactivated or silenced the pathway, leading to the accelerated accumulation of abnormal blood cells. Most importantly, the study also revealed that the reactivation of the silenced genes in the pathway blocked the disease, providing additional support for the potentially crucial role that Notch might play in the development of cancer.

In a commentary accompanying the study in Nature, Demetrios Kalaitzidis and Scott A. Armstrong of Dana Farber Cancer Institute and Children's Hospital Boston, note that the study defines a new role for Notch signaling as a suppressor of leukemia development. They note that further research is needed to understand the intricacies of Notch signaling in normal and cancerous tissue, which will help determine "the best approaches to manipulating this pathway for optimal therapauetic response."

This research study was funded by the Howard Hughes Medical Institute.

Email or share this story:

Detecting lung cancer early: Researchers lay foundation for future blood test

ScienceDaily (May 16, 2011) — A person's blood reveals whether he or she has lung cancer, according to researchers at the University of Bonn in Germany. In collaboration with colleagues at the Cologne University Hospital, they are developing a blood test for smokers which could save human lives in the future, since the earlier a lung tumor is detected, the better the chances of survival are.

See Also:Health & MedicineLung CancerLung DiseaseDiseases and ConditionsBrain TumorColon CancerCancerReferenceMetastasisLung cancerTumor suppressor geneTumor

The study has just been published in the journal Clinical Cancer Research.

Scientists working with Professor Dr. Joachim L. Schultze have identified over 480 molecules whose concentration in the blood changes when a person develops lung cancer. These molecules are present in the blood cells either in increased or decreased quantities. "In lung cancer patients, typical patterns which can be detected with a measuring program thus emerge," explains Prof. Schultze. The molecules are nucleic acids which form in the body when certain genes are transcribed.

The changes in the blood also occur if the tumor is still in a very early stage. In lung cancer, there are four different stages, explains Prof. Schultze: "The prognosis for patients in stage 3 and 4 is still very poor even today; even with the most modern therapies, the point of death can only be postponed." Lung cancer in stage 1, on the other hand, can be treated surgically and it can even be cured in many cases. "Today, however, a tumor is seldom detected so early, namely in only about 15% of all cases. If a simple screening blood test would increase this percentage, a large proportion of lung cancer patients could survive," says Prof. Schultze. By contrast, to date, over 80% of all lung cancer patients die within two years after diagnosis, since the tumor is already too far advanced.

Screening for lung cancer: Results within a day

In the future, a lung cancer screening test may become part of routine practice: The doctor takes a blood sample from his/her patient, and within 24 hours, he knows with a high degree of certainty whether the patient has lung cancer or not − even if the patient does not yet have any symptoms.

For many years, the team working with Prof. Joachim Schultze has investigated the blood of over 200 smokers. About half of them had lung cancer; the others were either entirely healthy or suffered from another lung disease. "It was important to us that a subsequent test not only be able to differentiate lung cancer patients from healthy subjects, but also from persons with chronic lung diseases." The researchers then examined the research subjects' blood using biochips for certain nucleic acids and in doing so, they found the typical patterns.

The researchers are presently planning an analogous but much larger study with ten times as many patients, in order to confirm the results. If the present results prove to be true in such a study, there would no longer be anything standing in the way of developing the blood test to the point of being ready to be put on the market.

Email or share this story: