A study published today in the December issue of the European medical journal Anticancer Research demonstrates that an ingredient used in a common cough suppressant may be useful in treating advanced prostate cancer. Researchers found that noscapine, which has been used in cough medication for nearly 50 years, reduced tumor growth in mice by 60% and limited the spread of tumors by 65% without causing harmful side effects.

Prostate cancer is the most common cancer among men in the United States. The American Cancer Society estimates that 186,320 men will be diagnosed with prostate cancer in 2008 and 28,660 will die from it. One man in 6 will get prostate cancer during his lifetime. Although slow-growing in most men, the cancer is considered advanced when it spreads beyond the prostate. There is no known cure.

The laboratory study was a joint effort by Dr. Israel Barken of the Prostate Cancer Research and Educational Foundation, Moshe Rogosnitzky of MedInsight Research Institute, and Dr. Jack Geller of The University of California San Diego. Noscapine has previously been studied as a treatment for breast, ovarian, colon, lung and brain cancer and for various lymphomas, chronic lymphocytic leukemia and melanoma. This study, however, is the first to demonstrate its effectiveness in treating prostate cancer.

Noscapine is a naturally-occurring substance, a non-addictive derivative of opium. As a natural substance, noscapine cannot be patented, which has limited the potential for clinical trials. Rogosnitzky notes that drug companies are generally unwilling to underwrite expensive clinical trials without being able to recoup their investment. A synthetic derivative of noscapine has been patented but has not yet reached the clinical testing phase.

Since noscapine is approved for use in many countries as a cough suppressant, however, it is available to doctors to prescribe for other uses as well. This common practice is known as “off-label” prescription. Noscapine is increasingly being used off-label to treat a variety of cancers. Dr. Barken used noscapine to treat a handful of prostate cancer patients before retiring from clinical practice. Encouraged by the success of these treatments, his foundation funded the laboratory study being reported in the December 2008 edition of Anticancer Research.

As founder and medical director of the Prostate Cancer Research and Educational Foundation in San Diego, Dr. Barken is encouraging academic institutions to follow up this successful laboratory research with a human clinical trial. He has pioneered a web-based patient tracking system that will greatly reduce the cost of the trial while cutting the time necessary to complete the study. Using the web-based tracking system will also allow doctors outside the U.S. to enroll patients in the research.

Rogosnitzky, director of research at MedInsight Research Institute, points out the significant advantages that noscapine could present as a treatment for prostate cancer. “Noscapine is effective without the unpleasant side effects associated with other common prostate cancer treatments. Because noscapine has been used as a cough-suppressant for nearly half a century, it already has an extensive safety record. This pre-clinical study shows that the dose used to effectively treat prostate cancer in the animal model was also safe.”

Hormone therapy and chemotherapy, along with radiation and surgery, are currently used to slow the progression of advanced prostate cancer. Side effects resulting from these treatments include impotence, incontinence, fatigue, anemia, brittle bones, hair loss, reduced appetite, nausea and diarrhea. No toxic side effects were observed in the laboratory study of noscapine.

Source

In the past decade some incredible steps forward have been taken in the treatment and cure for cancer. Now, Cornell Researcher Michael King is hoping to add one more to the list.
A new invention he is calling a lethal lint brush that can be implanted into the body to catch cancerous cells in the blood stream and destroy them may be a viable alternative to the painful and dangerous radiation treatments currently dominating Oncology.

Using a small tubelike container, the “lint brush” would be implanted into a blood vessel to filter the cancerous blood cells from the healthy ones. Once they had been separated, a protein called TRAIL (or Tumor Necrosis Factor Related Apoptosis-Inducing Ligand) would be released, causing the cells themselves to be destroyed, effectively killing off the cancer itself.

It may sound simple, but this microscopic device is much more complex then it sounds.

“It’s a little more sophisticated than just filtering the blood, because we’re not just accumulating cancer cells on the surface,” King told reporters. “This has never been tried before. It’s a whole new way of approaching cancer treatment.

The method has not yet been tested in humans.

A protein that shields tumor cells from cell death and exerts resistance to chemotherapy has an Achilles heel, a vulnerability that can be exploited to target and kill the very tumor cells it usually protects, researchers from the University of Illinois at Chicago show in a new study published in the Dec. 9 issue of Cancer Cell.

Akt is a signaling protein, called a kinase, that is hyperactive in the majority of human cancers.

“Akt is perhaps the most frequently activated oncoprotein (cancer-promoting protein) in human cancer,” says Nissim Hay, professor of biochemistry and molecular genetics at the UIC College of Medicine. Pharmaceutical companies have been trying to find ways to inhibit Akt to improve cancer therapy, he said, but most candidate drugs have acted too broadly and proved toxic.

“One of Akt’s major functions in tumor cells is promoting cell survival,” Hay said. “Tumor cells with hyperactive Akt are not only resistant to the external stresses that can induce cell death but also to chemotherapy.”

But Akt is also required for metabolism and the proliferation of cancer cells, and it was as a byproduct of its role in metabolism that the researchers were able to exploit Akt hyperactivity against the tumor cell.

“We found that cells with hyperactive Akt have increased intracellular levels of reactive oxygen species (ROS) and at the same time impaired ability to scavenge ROS,” Hay said. These ROS are highly reactive byproducts of metabolism that can damage the cell. Cells usually respond to high levels of ROS by undergoing cell suicide, or apoptosis.

“And, to our surprise, we found that although Akt can protect cancer cells from many of the external signals that would ordinarily induce cell death, including many chemotherapy drugs, it cannot protect from ROS inducers,” said Hay.

The researchers found that if they treated cancer cells with chemicals that raise ROS levels, the cells die. Akt could not protect cells from this form of apoptosis and, indeed, because Akt impaired the normal ROS scavenging in the cell, hyperactive Akt actually had the effect of making the cells more vulnerable to these ROS inducers. This enabled selective killing of cancer cells, expressing hyperactive Akt, and not normal cells.

The researchers also devised another strategy to exploit Akt’s Achilles heel to successfully target and kill cancer cells.

An FDA-approved chemotherapy drug called rapamycin can be used to arrest cell tumor growth. A drawback of this drug is that it doesn’t kill the cells, it just arrests the growth of the tumor. When the drug is removed the tumor may grow again.

“Rapamycin’s other drawback is complicated feedback regulation that we turn to our advantage,” Hay said. “It turns out rapamycin’s target and Akt talk to each other in the cell.” If the rapamycin target is hyperactive, Akt is inhibited, and if Akt is active, the rapamycin target is activated.

“So even though cancer cells treated with rapamycin stop dividing, they activate Akt, which makes the cells more resistant to other chemotherapy drugs,” said Hay. “But we use that to our advantage. Because overactivation of Akt sensitizes the cells to ROS mediated cell death, if we treat the cells with ROS inducers and rapamycin together we can now kill the cells, not just arrest their growth.”

The new study “provides a proof of the principle that Akt’s Achilles heel — a consequence of its role in metabolism — can be exploited in at least these two ways to selectively target and kill cancer cells,” Hay said.

Source: University of Illinois at Chicago

A Florida State University College of Medicine research team led by Yanchang Wang has discovered an important new layer of regulation in the cell division cycle, which could lead to a greater understanding of the way cancer begins.

Wang, an assistant professor of biomedical sciences at the College of Medicine, said the findings will lead to an improved ability to diagnose cancer and could lead to the design of new drugs that kill cancer cells by inhibiting cell reproduction. His paper on the discovery has been published in the journal Proceedings of the National Academy of Sciences.

“The correct timing of chromosome segregation during cell division is necessary to ensure normal, healthy growth,” Wang said. “Now we have discovered a previously undetected layer of regulation in how the chromosomes separate, which helps to ensure the correct timing and decreases the potential for the formation of cancerous growth.”

The cell division cycle is a collection of tightly regulated events that lead to cell duplication. The most important events are the doubling of the hereditary information encoded within a set of chromosomes, and the division of that duplicated information into two daughter cells that are genetically identical to each other and the mother cell.

The correct order of cell-cycle events is essential for successful cell division. Wang’s article addresses the role of a particular protein enzyme, Cdc14, in ensuring that cell division events occur in exactly the right order.

Defects in the regulation of the order of events can lead to cell death or the alteration of genetic information, which contributes to the formation of cancerous cells.

Tomatoes genetically modified to be rich in antioxidants called anthocyanins appeared to extend the life spans of cancer-prone mice, a European study finds.

The modified tomatoes were created by adding two genes (Delila and Rosea1) from the snapdragon flower. The anthocyanins, which belong to the flavonoid class of antioxidants, gave the tomatoes a peculiar purple color.

“The two genes we have isolated are responsible for flower pigmentation and, when introduced in other plants, turned out to be the perfect combination to produce anthocyanins, the same phytochemical found in blueberries,” study author Eugenio Butelli, of the FLORA project, said in a news release.

Chemical tests revealed that the “purple tomato has a very high antioxidant activity, almost tripled in comparison to the natural fruit,” making it very useful to study the effect of anthocyanins, Butelli said.

The researchers fed a powder obtained from the purple tomatoes to mice that lacked the p53 gene, which helps protect against cancer. These mice had an average life span of 182 days compared to 142 days for p53-deficient mice fed a standard diet.

The findings were published in the Oct. 26 issue of  Nature Biotechnology.

The study authors emphasized this is a preliminary study, and much more research needs to be done before there’s any possibility of human trials.

Source

A new anti-cancer compound that works by blocking a part of the cell’s machinery that is crucial for cell division has shown promising results in a phase I clinical trial in patients who have failed to respond to other treatments. Now it is going forward into a phase II clinical trial programme. In addition, the compound will also be tested in combination with other anti-cancer drugs to see whether combined therapies could be even more effective.

Professor Patrick Schöffski told the 20th EORTC-NCI-AACR [1] Symposium on Molecular Targets and Cancer Therapeutics in Geneva today (Wednesday 22 October) that after 50 patients had been given the compound BI 6727 in doses ranging from 12 to 450 mg, two patients with advanced bladder and ovarian cancers had shown confirmed partial responses and a further 32% of the patients had stable disease.

“The results so far indicate that BI 6727 is well tolerated by patients, with no serious side-effects detected. We have observed encouraging anti-tumour activity, which we would not necessarily expect to see in a phase I trial, and which warrants investigation in further clinical trials,” said Prof Schöffski, who is professor of medical oncology and head of the Department of General Medical Oncology at the University Hospitals Leuven (Belgium). [2]

BI 6727 is one in a series of compounds developed by Boehringer Ingelheim that work by inhibiting the action of a protein called Polo-like kinase 1 (Plk1), high levels of which are present in human tumours, but not in normal tissue. Plk1 is involved in cell growth; inhibiting it leads to abnormal mitotic spindles – the structures that separate the chromosomes into daughter cells during cell division – and this disrupts cell division, inhibiting the growth of tumour tissue.

“Plk1 inhibitors are targeted, cell cycle blockers that lead to spindle defects by inhibiting a key regulator of mitosis. They act on the mitotic spindle in a completely different manner compared to established anti-cancer agents such as vinca alkaloids or taxanes that directly bind to structural components of the mitotic spindle. Due to high levels of Plk1 in tumour cells compared to surrounding healthy tissue, compounds such as BI 6727 are effectively targeting dividing cancer cells,” said Prof Schöffski. “The results from this phase I trial suggest that BI 6727 potentially is a ‘first in class’ Plk1 inhibitor and the anti-tumour activity we have seen supports Plk1 as a therapeutic target.”

Preclinical data also presented at the meeting (abstract no: 430) show highly selective target inhibition and cellular activity at very low concentrations for this compound. BI 6727 shows excellent efficacy in multiple xenograft models of human cancer and its distinguishing features are its pharmacokinetic characteristics (what the body does to the drug) that allow for long-lasting tumour exposure.

The objectives of the phase I trial had been to assess the maximum tolerated dose of BI 6727 and its overall safety, the pharmacokinetics, and preliminary efficacy. Each treatment consisted of a single, one-hour infusion of the drug and it was given to sequential groups of three to six patients with advanced or metastatic solid tumours. If the cancer did not progress, further treatments were given at three-week intervals. The average number of treatments per patient was four, and at least 16 courses of treatment were given to two patients. The maximum tolerated dose was 400 mg.

The main adverse side effects of the drug were blood-related. Reduced white blood cells (neutropenia) or platelets (thrombocytopenia) were a result of Plk1 inhibition in normal cells and were both treatable and reversible events. About ten per cent of patients suffered from fatigue, mostly mild to moderate.

Speaking in September before the symposium started, Prof Schöffski said: “I will present the most up-to-date responses at the Geneva meeting, but, so far, one patient with urothelial [bladder] cancer has had clinical benefit for more than 16 cycles with BI 6727 and achieved confirmed partial response with the tumour shrinking by 42% within four cycles. Previously, this patient had failed other standard and experimental treatments. The cancer has not progressed since BI 6727 therapy started.

“A second patient with ovarian cancer had a confirmed partial response after two and four cycles, but her disease progressed at the sixth cycle. Previously, she had been treated with several courses of standard ovarian cancer treatments, including taxanes and cisplatinum.

“The initial part of the trial is completed, and now we have recruited a further 12 patients to compare different durations of infusion of the drug. We expect to have results from this soon.”

Prof Schöffski, who will be giving an invited “state of the science” lecture on Plk1 at the Geneva symposium, said the results for BI 6727 so far were promising. “This agent is among the few Polo-like kinase inhibitors in early clinical development. Boehringer Ingelheim has advanced this compound from its Plk1 inhibitor portfolio into phase II, due to favourable pharmacology and the promising safety and efficacy seen in this phase I trial.”

ECCO-the European CanCer Organisation

The 3-D structure of the virus, known as Seneca Valley Virus-001, reveals that it is unlike any other known member of the Picornaviridae viral family, and confirms its recent designation as a separate genus “Senecavirus.” The new study reveals that the virus’s outer protein shell looks like a craggy golf ball — one with uneven divets and raised spikes — and the RNA strand beneath it is arranged in a round mesh rather like a whiffleball.

“It is not at all like other known picornaviruses that we are familiar with, including poliovirus and rhinoviruses, which cause the common cold,” says the study’s senior author, Associate Professor Vijay S. Reddy, Ph.D., of The Scripps Research Institute. “This crystal structure will now help us understand how Senecavirus works, and how we can take advantage of it.”

The Senecavirus is a “new” virus, discovered several years ago by Neotropix Inc., a biotech company in Malvern, Pennsylvania. It was at first thought to be a laboratory contaminant, but researchers found it was a pathogen, now believed to originate from cows or pigs. Further investigation found that the virus was harmless to normal human cells, but could infect certain solid tumors, such as small cell lung cancer, the most common form of lung cancer.

Scientists at Neotrophix say that, in laboratory and animal studies, the virus demonstrates cancer-killing specificity that is 10,000 times higher than that seen in traditional chemotherapeutics, with no overt toxicity. The company has developed the “oncolytic” virus as an anti-cancer agent and is already conducting early phase clinical trials in patients with lung cancer.

But the researchers still did not know how the virus worked, so they turned to Reddy. He and his Scripps Research team, especially Sangita Venkataraman, Ph.D., a postdoctoral researcher, determined the Senecavirus crystal structure.

Reddy describes the differences they found between other picornaviruses and the Senecavirus as like variations among car models of the same manufacturer. “The chassis is the same, but the body style is different,” he says. “How the body of a virus is shaped determines how it infects cells.”

The structure of the Senecavirus is also depicted at http://viperdb.scripps.edu/, the “Virus Particle Explorer” developed at Scripps Research by Reddy and his colleagues. The online database is a worldwide resource for information on the structure of viral particles; it contains details of 253 viruses to date.

Once the structure of Seneca Valley Virus-001 was solved, researchers went on to identify several areas on the viral protein coat that they think might hook onto receptors on cancer cells in the process of infecting them. The researchers are now conducting further investigations on this process. “It will be critically important to find out what region of its structure the virus is using to bind to tumor cells, and what those cancer cell receptors are,” Reddy says. “Then we can, hopefully, improve Senecavirus enough to become a potent agent that can be used with many different cancers.”

The research was supported by grants from the National Institutes of Health.

Researchers at the University of Toronto have shown that the EBNA1 protein of Epstein-Barr virus (EBV) disrupts structures in the nucleus of nasopharyngeal carcinoma (NPC) cells, thereby interfering with cellular processes that normally prevent cancer development. The study, published October 3rd in the open-access journal PLoS Pathogens, describes a novel mechanism by which viral proteins contribute to carcinogenesis.

EBV is a common herpesvirus whose latent infection is strongly associated with several types of cancer including NPC, a tumor that is endemic in several parts of the world. With NPC only a few EBV proteins are expressed, including EBNA1. EBNA1 is required for the persistence of the EBV genomes, however, whether or not EBNA1 directly contributes to the development of tumors has not been clear, until now.

In this study Frappier and her team examined PML nuclear bodies and proteins in EBV-positive and EBV-negative NPC cells. Manipulation of EBNA1 levels in each cell type clearly showed that EBNA1 expression induces the loss of PML proteins and PML nuclear bodies through an association of EBNA1 with the PML bodies. PML nuclear bodies are known to have tumor-suppressive effects due to their roles in regulating DNA repair and programmed cell death, and accordingly, EBNA1 was shown to interfere with these processes.

The researchers conclude that there is “an important role for EBNA1 in the development of NPC, in which EBNA1-mediated disruption of PML nuclear bodies promotes the survival of cells with DNA damage.” Since EBNA1 is expressed in all EBV-associated tumors, including B-cell lymphomas and gastric carcinoma, these findings raise the possibility that EBNA1 could play a similar role in the development of these cancers. The cellular effects of EBNA1 in other EBV-induced cancers will require further investigation.

http://www.plospathogens.org/doi/ppat.1000170

UCI-led study shows effectiveness of first treatment to target and stop ovarian cancer cell growth

Women with recurrent ovarian cancer can be helped by an experimental therapy using a drug already touted for its ability to fight other cancers, a finding that provides hope for improved treatment of this deadly disease.

Dr. Bradley Monk, a UC Irvine gynecologic oncologist who led the worldwide phase III clinical trial, said trabectedin is the most recent addition to a short list of active drug therapies for recurrent ovarian cancer. He presents study results Sept. 15 at the 33rd Congress of the European Society for Medical Oncology in Stockholm.

“These are exciting results because positive trials in recurrent ovarian cancer are rare and have almost always led to federally approved treatments,” said Monk, an associate professor who studies and treats ovarian cancers at the Chao Family Comprehensive Cancer Center at UC Irvine. “This treatment undoubtedly will be evaluated carefully by the U.S. Food and Drug Administration and, if approved, will give women with ovarian cancer another much needed option.”

Phase III studies are multicenter trials on large patient groups designed to be the definitive assessment of a drug’s effectiveness. Such a study is often the last step before a drug is reviewed by a regulatory agency like the FDA for approval as a safe, effective treatment.

In this trial, an international group of researchers treated 672 women whose ovarian cancer had progressed after first-line treatment. Half the women received a combination therapy of trabectedin and a chemotherapy drug called pegylated liposomal doxorubicin. The other half received the chemotherapy drug alone, which is standard treatment in these cases.

In patients on the combination therapy, researchers found no progression of the cancer for an average of 7.3 months, as compared to 5.8 months for those treated with the single drug. For those who had relapsed more than six months after the first-line therapy, the median progression-free time was 9.2 months for the combination treatment, as compared to 7.5 months for the other patients.

Under the brand name Yondelis, trabectedin is approved in Europe and South Korea for treating advanced soft tissue sarcoma. In addition to the phase III ovarian cancer trial, it is being studied in smaller, phase II trials for prostate, breast and pediatric cancers.

Trabectedin is a synthetic version of a compound isolated from the sea squirt, a tubular sea animal used in a number of medical studies. It binds to the DNA of a cancer cell and blocks its ability to multiply, thus killing the cells and shrinking tumors.

When ovarian cancer is detected early – when it is confined to the ovaries – more than 90 percent of women will live at least five years, according to the American Cancer Society. Only about 20 percent of cases are detected that early. If the cancer is detected after it has spread, only about 30 percent of women survive five years. Each year, approximately 20,000 American women are diagnosed with ovarian cancer and about 15,000 die of the disease.

University of California - Irvine

Anti-tumor therapy guided by endoscopic ultrasound may allow doctors to fight cancer more safely and effectively

The chairman of EU󋈈 today announced that investigational research on a therapeutic technique that will allow physicians to directly inject malignant tumors with cancer fighting agents from inside the body will be presented at the 16th International Symposium of Endoscopic Ultrasonography (EUS2008) in San Francisco on September 12-13. This technique, which uses a flexible gastrointestinal endoscope with a miniature ultrasound transducer on the tip to guide a small needle directly into a tumor, could prove to be a safer and more effective approach to administering chemotherapy since it allows doctors to deliver therapy right to the tumor and avoid damaging normal surrounding tissues. Injecting drugs directly into the cancer using endoscopic ultrasound (EUS) in combination with systemic chemotherapy to kill cancer cells that have spread may prove to be a more effective approach to some cancers.

EUS combines endoscopy and ultrasound in order to obtain the most accurate, high resolution images and information about the digestive tract and the surrounding tissue and organs. A more advanced form of EUS, called curvilinear EUS, allows doctors to operate within the lumen of the gut while at the same time detect, biopsy and treat lesions and tumors that lie outside the intestinal wall. This technique is particularly useful in patients with pancreatic, esophageal and rectal cancer.

“Curvilinear endosonography will likely become the dominant technology within the field of EUS,” said co-chairman of EUS2008, Robert Hawes, M.D., Professor of Medicine and Peter Cotton Chair for Endoscopic Innovation at the Medical University of South Carolina. “The potential for accurate diagnosis using ultrasound-guided biopsy, precise staging with high resolution ultrasound images and then the enormous opportunity for new therapies with the curvilinear endoscope is why we are focusing this meeting on the use of this instrument alone.”

Used in conjunction with real time imaging, EUS can help physicians to detect blood flow in blood vessels in and around tumors as well as detect and biopsy tumors and lymph nodes as small as 3-5 mm. This allows doctors to avoid puncturing blood vessels when sampling tissue, get the most accurate view of the cancer and know exactly what stage a cancer is in for optimal therapy for treatment. This could save cancer patients with late stage disease from going through unnecessary surgery. EUS may also play a role in the future of minimally invasive surgery (MIS). A new paradigm in MIS is called natural orifice translumenal endoscopic surgery (NOTES®). This entails using the stomach as a window to the abdominal cavity rather than the skin. EUS could play an important role in helping surgeons gain safe access to the abdominal cavity as part of NOTES.

EUS 2008 will be devoted to teaching current applications of curvilinear endoscopic ultrasonography in order to encourage endosonographers and gastroenterologists to become proficient in these procedures, enhance their techniques and increase collaboration with oncology surgeons. This meeting has a rich tradition dating back to the first meeting held in Stockholm, Sweden in 1982. The meeting has evolved as technology has changed and improved along with the exponential growth of endosonographers around the world.