Results obtained in a phase I clinical study of the new drug were presented in Berlin, on November 19th, at the 22nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics. ACE-041 aims at the receptor known as ALK-1 (activin receptor-like kinase-1), which is responsible for regulating the formation of new networks containing blood vessels that are needed for the growth of tumours. This process is known as angiogenesis. Existing anti-angiogenic drugs, including sunitinib, bevacizumab and sorafenib are targeting other angiogenesis receptors like VEGF, while ACE-041 is among the first drugs to target the ALK-1.

Professor Sunil Sharma, who is the Jon and Karen Huntsman Presidential Professor of Cancer Research at the Huntsman Cancer Institute of the Utah University in Salt Lake City, USA, said that the connection between angiogenesis and ALK-1 was made by discovering that mutations in the ALK-1 gene had caused a condition named HHT2 (hereditary haemorrhagic telangiectasia 2, characterised by diminished formation of capillary beds, which causes red markings at the level of the skin.

A technology company in Cambridge, Massachusetts, USA, Acceleron Pharma, has designed ACE-041 aiming to inhibit ALK-1 signalling and has asked Professor Sharma to be one of the investigators who would conduct the first-in-man phase I clinical test of the drug in order to see if it really would halt tumour angiogenesis.

Professor Sharma said that since ALK-1 was transiently expressed on proliferating cells lining the inner surface of the blood vessels (endothelial cells), while VEGF receptors were constitutively expressed on endothelial cells and other types too, it would be a more selective target when trying to inhibit angiogenesis. ALK-1 expression on the vasculature of the tumour has been noticed on biopsy samples of a wide range of tumours.

The phase I of the study comprised patients with a diversified range of advanced solid tumours that already spread to other parts of the body or simply were inoperable like multiple myeloma, neck and head cancers, NSCLC (non-small cell lung cancer) and carcinoid tumours (carcinoma type neuroendocrine tumours usually originating in the appendix or small intestine). Many of the patients had been unsuccessfully treated with a series of other treatments, which included anti-VEGF drugs, before this trial. ACE-041 has been administrated via subcutaneous injections.

Professor Sharma said that, early in September, 25 patients have been included in the study and ACE-041 dose level has been escalated from 0.1 mg/kg to 4.8 mg/kg. In the case of a patient with neck and head cancer, the response was partial, while three patients have shown positive responses as determined by FDG-PET scans. ACE-041 has been well tolerated by the patients, with some adverse events like peripheral oedema, anaemia, headache, nausea and fatigue.

Seeing many signs of efficacy during the trial has been quite encouraging for the medical team, particularly because of the structure of the study population. They were patients with end-stage cancer, already treated with and refractory to multiple standard therapies. It has equally been encouraging to note signals of activity of ACE-041 in a wide series of tumour types, thus confirming the hypothesis that ACE-041 may really act against tumours with agiogenic activity, no matter what histology they had. Another important aspect to be noted was the demonstration of the significant activity with ACE-041 monotherapy during the study, which leads to expectations of more efficacy in future studies including ACE-041 combined with other therapies.

Professor Sharma and his team planned further investigations related to the safety and tolerability of ACE-041 in an additional group of cancer patients and look forward to start a phase II study in 2011.

According to Professor Sharma, the anti-VEGF angiogene inhibitors, which include sunitinib, bevacizumab and sorafenib, have represented an important contribution to the armamentarium of therapies against cancer. However, the efficacy is in a way limited because tumours could eventually develop an ability to simulate angiogenesis using non-VEGF angiogenic factors. Serious side-effects appear from effects on blood vessels found in normal tissues. ACE-041 inhibits angiogenesis in a totally different way and therefore it might have synergistic efficacy with VEGF-based inhibitors. It may be effective for patients who have manifested resistance to VEGF inhibitors.

This environmental report is just a part of the process of taking care of the continuous and newly discovered problems regarding the pollutant agents of the environment and cancer. Moreover, the scope of the report is to shed more light on the principles, mission, values, objectives and various roles of the American Cancer Society on issues such as those mentioned before: pollution and malignant tumors prevention.

As the co-chair of the subcommittee and chairman of the Department of Preventive Medicine within the Keck School of Medicine of University of Southern California, medical doctor Jonathan Samet explains the problems regarding the environmental pollution agents affecting the air, water, food and thus, customer products represent issues on general public care and high unknowns. He also adds that their report aims to put the pollution agents of the environment in a greater relationship with preventing malignant tumors. The relationship focuses on reducing the smoking habit of the population, improving nutritional behavior, increasing the physical activities, maintaining a proper body weight and come up with vaccines that counteract the infections which may cause cancers.

The other co-chair of the subcommittee is also volunteer president of the American Cancer Society. Her name is Elizabeth “Terry” T.H. Fontham and she stated that the exposure levels of the population to chemical and pollution agents affecting the environment are much lower than the levels linked to the showed predisposition to developing malignant tumors in the jobs people have and other daily settings. However, the concern raised by the low exposure levels has to do with the fact that the number and types of pollution substances are increasing and may prove in the future to get out of the population`s control. In addition, the problems related to the fact that even low exposure levels bring some contribution to the cancer developing cases cause more reasons for distress considering the high number of persons who are daily exposed to the environmental pollutants.

The subcommittee`s report states that the scientific problems related to the exposure of people to the environmental pollutants represent complex issues just like increase in the number of landscape technologies which are utilized to analyze the chemical carcinogenicity. In spite of the capability of the nowadays tools used to identify and categorize proves for carcinogenicity, the subcommittee`s article states that there exist three main problems which constrain them from using them because there is a limited quantity of resources which are allotted to function those specific systems and from a scientific point of view, the environmental problems are complex and uncertain.

The report`s concerns about cancer vary and are related to malignant tumors prevention. There is a high need for new stratagems related to the tests done to evaluate the environment`s toxicity, comprising also the evaluation of carcinogenicity. These new strategies could be incorporated in such a manner as to assure a more efficient and effective screening process of a higher number of chemical agents which affect people daily. In addition, exposure to occupational and community settings should be regulated by some standards. The subcommittee draws attention on the need to support investigations aimed at identifying and decreasing the number of hazards provoked by carcinogens. Furthermore, the institutions that determine and implement standards for the environment must meet proper financing and appropriate technology in order to be near the scientific evolution and upgrade their set standards according to the new available data.

Even though some exposure cannot be avoided, this type of exposure must be somehow diminished and even stopped in the cases where it is possible to do so. In addition, the population must receive information about these matters in order to know their health status and risk of cancer or other diseases. Last, but not least, the media communication must make people aware of the situation of the exposure in an accurate manner and not to exaggerate or diminish the importance and level of environmental pollution factors.

The subcommittee’s report states that in order to create and implement this new initiative in order to assure the acquiring of more knowledge regarding the association between the levels of exposure to environmental pollution agents and the predisposition to various types of cancers, the American Cancer Society is going to further develop its long-run commitment to preventing malignant tumors. In addition, the American Cancer Society is also keen on studying these problems more thorough in order to discover new ways in which the initiative could bring more benefits in an effective and efficient manner.

The investigation was released in the Alcoholism: Clinical and Experimental Research edition. The study comprises the researchers` findings regarding how alcohol triggers the epithelial-to-mesenchymal transition. During this transition, the mild cancerous cells transform in aggressive one and start invading the whole body in a process entitled metastasis.

As assistant professor Christopher Forsyth from the medicine and biochemistry division within the Rush University Medical Center explains the information provided by the team of investigators led by him is the first of its kind. This is due to the fact that their data presents the pathway in which alcohol stimulates specific triggers within a cell which are implicated in the metamorphosis into an aggressive form of the cells.

The notion of epithelial-to-mesenchymal transition is a highly researched matter nowadays due to the fact that it represents one of the processes involved in the mechanism of cancer spreading in the whole organism. An amalgam of laboratory investigations and clinical trials shows that this epithelial-to-mesenchymal transition is a prime factor in triggering the aggressiveness of the cancerous cells.

Professor Christopher Forsyth stated that the malign cells acquire a dangerous characteristic in the moment when they start spreading in the whole body. The operations can resection a malign tumor, but the aggressive cells have the ability to spread out in the whole human organism and conquer it. If medical doctors could stop this process, they would be able to limit the spreading of the malignant tumors.

The team of investigators put alcohol in cellular lines coming from colon and breast cancers and observed them in order to find the biochemical distinct signs of the epithelial-to-mesenchymal transition also including the presence of both Snail which is a transcription agent and the receptor concerned with the growth agent of the epidermis. The Snail represents the epithelial-to-mesenchymal transition`s control factor. On experiments undergone on mice, it was observed that if there is an over-expression of this factor, multi tumors are prone to develop. The second agent, the epidermal growth one is just like a drug for the cancer cells, they require large quantities of it.

The testing undergone in laboratories proves that alcohol triggered both factors and also other biochemicals agents related to the epithelial-to-mesenchymal transition. The trials also proved that the cells which were put in alcohol lost their strong links to adjacent cells, a characteristic which resembles the metastasizing process of the malign tumors.

Furthermore, professor Christopher Forsyth`s team of researchers discovered that the similar group of biomarkers was triggered in healthy intestinal cells which were put in alcohol. In addition to the aggressive metamorphosis alcohol triggers in cancer cells, this finding could mean that alcohol may also trigger the development of cancer.

As statistics show, the prostate tumors affect, commonly, male population over the age of fifty years. In the United States, the prostate cancer is the main malign disease affecting men. The high mortality rate caused by this type of cancer is due to the fact that the tumor cells develop fast and reaches metastasis, thus, affecting other organs in the human body.

One of the first signs of tumor cell development is the fact that the malign cells become connected to the blood flow of the human body in a process entitled intravasation. Conn and his team tried to take a closer look at this process and in order to achieve this, the investigators took a prostate carcinoma sample and managed to isolate the high and low circulation and spreading of the cancer cells. The cellular line from the prostate cancer tissue that was more expected to metastasize showed a big angiogenic feature. Furthermore, it was observed that this type of cells were more aggressive in spreading in the whole human body.

The cells that have pronounced metastatic characteristics create more levels of urokine plasminogen activator. The team of researchers discovered that in order to counteract and even stop the development, intravasation and imigration of the aggressive cancer cells in the organism, the levels of the urokine plasminogen activator should be lowered and this serine protease should be inhibited.

The team of investigators from the Scripts Research Institute drew as conclusion for their research that there is a strong relationship between the metastasis of the prostate cancer and the urokine plasminogen activator. After comparing the samples and their results and specifics, they stated that the secretion of VEGF and the urokine plasminogen activator aid the malign cells in their pathway to spreading to other organs in the body. Logically, these two agents are also some of the causes for cancer cells intravasation. Last but not least, the investigators stated that there is a relationship between the two factors and the angiogenesis and the linkage of the tumor cells into the blood flow of the infected organism.

The research team was led by Professor Doctor Tony Hunter from the Molecular and Cell Biology Laboratory and was aided in his study by: John Brognard, Zhongsheng You, Aaron Aslanian, Chris Coughlin, Robert T. Abraham, Marisa Dolled-Filhart and Gerard Manning.

As Professor Hunter states: “A lot of progress has been made in understanding the molecular details of checkpoint activation, but checkpoint termination, which is essential for the resumption of cell cycle progression, is less well understood.” This is why they undertook the study, in order to gather more information about this process and find out how they can diminish the resistance to chemotherapy of the cancer cells. By doing this, they would later be able to develop treatments with smaller side-effects based on the checkpoint exit mechanism. Researcher You-Wei Zhang states that if the doctors would be able to scan tumors to discover their resistance to chemotherapy, they would be able to adjust the treatment.

When the DNA is damaged, eukaryotes which copy DNA enable the checkpoint for DNA damaged cells to stall the process, allowing them time to recover from the interruption. In case the repairs do not take place, the cells may die or mutate into cancer. The main actor in this process is the Chk1 checkpoint protein. It reacts to hypoxia, cancer drugs that strive to damage the DNA of tumor cells and radiations. These factors affect the evolution of Chk1 and, in time, lead to the protein`s degradation. However, researchers have not discovered yet what triggers the disposal of Chk1 by the protein degradation mechanism.

You-Wei Zhang studied this protein and found out that when it is activated it brings to light a degron which is a string of amino acids. The degron attracts F box protein 6 which marks Chk1 with an enzyme group that degrades the proteins. This eliminates the Chk1 proteins and enables the cell life cycle to get back to the progression process. In the case of a long period of replication stop, the action of the enzyme complex will resume to kill the damaged cells. However, there are malign cells that counteract the effect of the enzymes and still manage to replicate. Doctor Hunter states: “Camptothecins are FDA-approved cancer drugs that induce replication stress and stop cancer cells dividing, but their clinical antitumor activity is very limited by the relatively rapid emergence of drug resistance, and the mechanisms are poorly understood. We wondered whether defects in the Chk1 destruction machinery might allow cells to ignore the effects of camptothecin and similar drugs used for chemotherapy.”

Researcher Zhang discovered by looking at cancer cell lines cultures and tissues from breast cancers that the levels of F box protein 6 were low when protein Chk1 was present in a large number and vice versa. Moreover, he proved that the two out of three camptothecin-resistant malign cellular lines located in the cell samples from the National Cancer Institute showed the same deficiencies in the degradation of Chk1 induced by camptothecin. This was the result of the small levels of F box protein 6. You-Wei Zhang states: “Chk1 and Fbx6 clearly play an important role for the regulation of the response to chemotherapy. One day, they could become an important prognostic marker that predicts patients’ responsiveness to drugs such as irinotecan, platinum compounds, and gemcitabine, while Chk1 inhibitors might increase tumor cells’ sensitivity to these drugs.” This shows that this kind of therapy may reduce and even annihilate the chemotherapy resistance of the malign cell. Moreover, it could mean that the quantities of cancer drugs given to ill patients may be reduced, therefore, minimizing their secondary and negative side-effects.

Leading the research team are: doctor Håkan Andersson, an oncologist from Sahlgrenska University Hospital and Ragnar Hultborn, professor at Sahlgrenska Academy and Lars Jacobsson, radiation physicist. The three hope to revolutionize the treatment against ovarian cancer. As they say: “There is a good chance of this treatment working, as the study indicates that a sufficient amount of the active substance reaches the tumor cells in the abdominal cavity without any measurable side-effects.”

The study was published in the Journal of Nuclear Medicine. Its primary purpose was to observe how the radioactive substance entered in contact with the human body and its distribution and side-effects. The research was carried out on nine women, all suffering from ovarian cancer.
The partnership of the two entities resulted in an innovative treatment for metastatic ovarian cancer. It consists of an injection with a radioactive isotope in the abdominal cavity. The substance attacks cancer cells. The isotope connects to the surface of the malign tissue and starts emitting alpha particles at a short range in order to counteract the DNA of the tumor cells and destroy them.

If in the past, treating ovarian cancer was done in such a way that left severe side-effects, the researchers hope that this innovative treatment will become in a few years available for patients suffering from ovarian cancer.

Oncologist Håkan Andersson wants to treat 80 women suffering from this type of cancer in their future research to further develop the cure. The injections with the radioactive isotope will be done as a complementary part of the traditional cancer treatment. In this way researchers hope to verify if this treatment has the same beneficial effects on human beings as it did in the animal experiments.

Coming to aid their research, the Swedish Research Council and the Swedish Cancer Society will give the research team a part of the fund they need in order to continue with their tests to treat ovarian cancer.

Professor Hochberg proved that H19 gene is expressed in over 33 different forms of cancer and he succeeded in isolating this gene in humans. Among the types of cancer it is expressed in, we mention superficial bladder carcinoma and pancreatic, ovarian and metastatic liver cancer.

This gene, according to researchers, is an important actor in the tumor development process by enabling tumor cells to survive under stress conditions. Among these stress conditions there are low serum and low oxygen levels, that are typical conditions of the environment in which cancerous cells develop.

The aspects discovered by this research make the scientist believe they can find a drug that can suppress the expression of H19 gene and in this way provide benefits that are competitive with existing treatment methods.

Yissum Research Development Company of the Hebrew University patented the research of Professor Hochberg. Yissum established BioCancell Inc. in 2005, a company that is now traded in the Tel Aviv stock exchange (TASE).

The Kaye Innovation Awards have been given annually since 1994, Professor Hochberg receiving one for this discovery. “Isaac Kaye of England, a prominent industrialist in the pharmaceutical industry, established the awards to encourage faculty, staff and students of the Hebrew University to develop innovative methods and inventions with good commercial potential which will benefit the university and society.”

Tej K. Pandita, Ph.D., a researcher with the Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital, and his colleagues want to know how a common genetic mutation makes cancer radiation resistant.

Cells pass through several phases as they grow and divide, each phase having its own checkpoints that assess whether a cell is healthy enough to continue with these two procedures. If the situation is perceived otherwise, signals from checkpoints should predict future steps to be taken, either repairing or death.

Pandita, associate professor of radiation oncology and of genetics, said “The defective checkpoints contribute to radioresistance. When a cell gets damaged by radiation, normally checkpoints will make it stop growing to repair the damage. If the checkpoints are working but the cell has a defective DNA repair system, the cell will be radiosensitive. But if the checkpoints don’t operate, the cell can bypass DNA repair and continue to grow and divide. Then the cells are radioresistant.”

In order for the tumours with PTEN mutations to increase radiation sensitivity, there will be needed further development of drugs that could correct the faulty checkpoints. This is a subject for further studies as the work continues.

This research was supported by Funding from National Institutes of Health.

The research, led by Dr. Andrew Berchuck, a gynecologic oncologist at the Duke Comprehensive Cancer Center, consisted in the examination of gene expression patterns in 166 ovarian cancer tissue samples, both from patients who had experienced long-term survival of over seven years and from patients who had died within three years of diagnosis. Using micro-arrays to examine over 22,000 probes of DNA, genes that were most predictive of survival were identified.

Regarding the outcome of the research, Berchuck stated:
“We found that certain patterns predicted long-term survival and others predicted a poorer prognosis in advanced stage cases. Cancers that were detected at an early stage almost always shared gene expression characteristics with advanced stage cases that were long-term survivors, suggesting a shared favorable biology. Our study showed that the ovarian cancers currently detected at an early stage have gene expression profiles that correlate with favorable outcome, rather than being representative of the entire spectrum of disease aggressiveness.

While these results could be seen as discouraging, it must be remembered that this information is an important piece of the ovarian cancer puzzle, and data like these that increase our understanding of the disease hopefully will eventually lead to breakthroughs in prevention, early detection and treatment of this deadly disease.”

Similar challenges are seen in the screenings of lung cancer and prostate cancer, where the method detects the disease using radiological imaging and/or blood markers but lets unclear if cancer-related deaths are prevented because screening preferentially detects more benign cancers that are much less likely to be fatal. No ovarian cancer screening test is yet approved, CA125 blood test and transvaginal ultrasound imaging currently being evaluated in clinical trials.

Adapted from materials provided by Duke University Medical Center.

The oncogene in question is in fact a mutation of the gene Myc, which normally is an important factor for the growth of organisms by cell division, regulating the production of a protein that controls the expression of up to 15 % of all human genes. When the mutation of the Myc gene occurs, cell proliferation goes array and apoptosis (the process of programmed cell death) is inhibited, which could lead to the formation of tumors.

Since the Myc gene does not have enzymatic activity of its own, the inhibition of the oncogene can’t be done trough pharmacological substances. The research team, led by Klaus Bister and Markus Hartl, think that the answer to this problem may come in the form of another gene, BASP1, which, as their experiments revealed, specifically inhibits the uncontrolled proliferation of Myc.

“Until now the precise biochemical function of BASP1 is unknown. However, in our experiments we have found clear evidence that Myc-induced cell transformation can be specifically inhibited by BASP1, and consequently, the gene functions as a tumor suppressor.”, stated Prof. Bister in regard of these new findings that could lead to the development of new tumor-suppressant drugs.