Chemotalk Newsletter

Chemotalk Newsletter, Vol. 64: August 1, 2013

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A Good August to you all.

NEW DRUG EFFECTIVE IN BRAIN CANCER

Robust data indicate that aldoxorubicin regressed brain tumor growth and more than doubled the average survival time compared with doxorubicin

CytRx Corporation, a biopharmaceutical research and development company specializing in oncology, today announced that aldoxorubicin, its more potent version of the widely used chemotherapeutic agent doxorubicin, demonstrated statistically significant efficacy in the treatment of rapidly growing human BRAIN (glioblastoma) CANCER in the brains of animals. Complete results from this favorable confirmatory trial, which was conducted in collaboration with Louisiana State University (LSU) School of Medicine, will be presented at the European Society for Medical Oncology.

"We are surprised and excited about the effectiveness demonstrated by aldoxorubicin in this particularly difficult-to-treat cancer," said Om Prakash, Ph.D., the study's principal investigator and Research Professor of Medicine, Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans. "It has been well documented that doxorubicin, although active against glioblastoma cancer cells in tissue culture, does not cross the blood-brain barrier, the body's natural defense system protecting the brain, to effectively treat patients with brain tumors. In fact, in our study doxorubicin was no more effective than saline in suppressing glioblastoma tumor growth. We have shown that aldoxorubicin uptake is confined only to the tumor in the brain and does not enter normal brain tissue. Thus, we would expect toxicity in the central nervous system to be negligible. Our conclusion from this trial is that aldoxorubicin has the potential to safely shrink glioblastoma tumors which could dramatically prolong the average survival time in patients. We initially had observed a similar effect of aldoxorubicin on glioblastoma in a preliminary study, and are quite pleased to have confirmed the result in a larger, well-controlled study that included native doxorubicin."

Dr. Prakash's main focus of his research efforts in the last few years has been to understand the pathogenesis and treatment of glioblastoma multiforme, the most malignant and the most deadly type of brain tumor. He is the corresponding author on several poster presentations in national/international meetings. More recently, he is the first author on a publication, Gliomas and Seizures in the Medical Hypothesis Journal (Prakash et al. 2012; 79:622).

"This trial produced remarkable results in a deadly cancer that virtually always returns regardless of whether treated with surgery, radiation, chemotherapy or a combination of methods," said CytRx President and CEO Steven A. Kriegsman. "Animals treated with aldoxorubicin survived on average more than twice as long as those treated with saline or doxorubicin.

Aldoxorubicin could provide an exciting new approach in how we attack brain tumors. These outstanding results support our plan to initiate a Phase 2b clinical trial with aldoxorubicin in patients with relapsed glioblastoma. We remain on track with expanding our aldoxorubicin clinical development activities and expect our progress to accelerate in the coming months and year," he added. If the data from the company's planned Phase 2b clinical trial for glioblastoma are positive, it plans to file for breakthrough therapy designation with the U.S. Food and Drug Administration, which could expedite marketing approval for aldoxorubicin.

Aldoxorubicin has shown to be superior to doxorubicin in seven different tumor types and animal models of cancer, including OVARIAN, LUNG, BREAST and PANCREATIC CANCER, as well as MULTIPLE MYELOMA, and has demonstrated activity in human trials for the treatment of SOFT TISSUE SARCOMAS and other cancers. Aldoxorubicin is the first drug candidate CytRx is developing based on a novel linker technology that has proven ability to allow attachment of multiple chemotherapeutic agents and is designed to provide both greater anti-cancer activity and to mitigate the toxicity that limits these agents' use.

About Glioblastoma Multiforme

Glioblastom multiforme (GBM) is the most common and most malignant brain tumor in adults and afflicts more than 12,000 new patients in the U.S. annually. Despite surgical resection, radiotherapy and chemotherapy, the median survival after diagnosis is about 12-14 months. Although the reason for treatment failure may depend upon several factors, limited efficacy of chemotherapeutic agents has been attributed to several contributing factors including insufficient drug delivery to the tumor site through the blood-brain barrier.

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FDA Oks LUNG CANCER DRUG

The FDA has handed oncologists another weapon in the fight against LUNG CANCER. The agency today approved afatinib, a targeted therapy for non-small cell lung cancer which will be tied to a diagnostic test to identify the portion of the late-stage patient population most likely to respond to the drug, which will be sold as Gilotrif. Patients taking the drug had an average rate of progression-free survival of 11.1 months compared to 6.9 months for the standard therapy arm. More impressively, patients with the two EGFR mutations studied survived 13.6 months without seeing their cancer get any worse. The drug was approved concurrently with therascreen, a diagnostic used to identify patients whose lung cancer cells express EGFR.

The drug is a tyrosine kinase inhibitor designed to coral proteins that drive cancer. It's most likely to work in patients whose tumors express EGFR exon 19 deletions or exon 21 L858R substitution gene mutations. And that's the kind of patient targeting that the FDA has been encouraging.

"Today's approvals further illustrate how a greater understanding of the underlying molecular pathways of a disease can lead to the development of targeted treatments," said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research. "Gilotrif is the second drug approved this year for patients with untreated metastatic non-small cell lung cancer whose tumors have the EGFR exon 19 deletions or exon 21 L858R substitution mutations." The first drug to be approved by the FDA was Tarceva.

Lung cancer has proven to be a tough target for drug developers and the prognosis for survival is often quite poor. But there are other drugs in the pipeline that may be added to oncologists' weapon chest in the not too distant future. Two of those drugs--the next-gen ALK inhibitor LDK378 and the immunotherapy nivolumab --have both been designated as breakthrough drugs worthy of VIP treatment at the FDA.

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FIGHTING A CUNNING CANCER OPPONENT

It was a classic eureka moment. In 2006 Mary Bebawy was listening to a lecture outside her area of research when suddenly the intellectual penny dropped. "My mind went elsewhere. I didn't hear the rest of the lecture," says the University of Technology, Sydney (UTS) cancer researcher and pharmaceutical scientist.

"Elsewhere'' in this case was to a possible explanation of how cancer cells rapidly become resistant to the arsenal of anti-cancer drugs tossed at them. It was as if they shared secrets with one another, she imagined. Seven years on that unexpected insight has proven correct. After teaming up with the scientist who sparked her eureka moment ­ Sydney University vascular immunologist Georges Grau ­ Associate Professor Bebawy has found that drug-resistant cancer cells really do communicate with other cells, healthy or otherwise. And they do so in a surprising way.

"We discovered that a resistant cancer cell can shed tiny vesicles, or micro particles, from its surface,'' Professor Bebawy explains, adding that inside these micro particles is genetic material and large molecules called proteins which confer drug resistance. In a nutshell, the proteins pump drugs out of a treated cell. "The micro particles dock onto a drug-sensitive cancer cell and within two hours they release their contents into the cell. As early as four hours later that cell is multi-drug resistant cancer cell," Professor Bebawy says.

But it gets worse. Not only can resistant cancer cells transfer resistance to drug-sensitive cells, they can also mop up and sequester cancer drugs from the blood stream, rendering them useless.

"The patients have roughly 50 per cent less drug in their body," she says. The implications are clear. Cancer cells are survivors. "I'm in awe of the inherent capacity of cells to survive. It's an evolutionarily conserved pathway. It's quite remarkable," says Professor Bebawy who now has National Health & Medical Research Council funding.

While cancer cells are cunning opponents, if Professor Bebawy and her team of 10 UTS doctoral students can tease out all their tricks it should be possible to design drugs able to circumvent them or tests that can detect developing drug resistance. The latter would help clinicians keep up with the adaptive cancer cells.

Working with collaborators such as Professor Grau and cancer specialists at Royal Prince Alfred and Concord hospitals, the UTS team is developing a blood test for identifying the resistance proteins in patients with MYELOMA, a bone marrow disease. Currently, the only way to do this is with highly invasive biopsies from the bone marrow.

It's early stages for clinical applications of the micro particle work but Professor Bebawy ­ who has seen cancer in her own family ­ is confident they're gaining the upper hand, based on a growing body of scientific evidence detailing the devious survival skills of cancer cells. So, today it's obvious cancer cells can communicate drug resistance to other cells. But as with any new field of research that wasn't the case in 2006. Just finding funding to explore this blue-sky hypothesis was tough. Eventually, the NSW Cancer Council took a chance. "In 2009 they gave me $120,000 per year for three years,'' Professor Bebawy says. "It allowed me to employ a research assistant and do the experiments. The fact they believed in me, I'm forever grateful."

That initial support enabled professors Bebawy and Grau and their colleagues to publish their first paper on the micro particle mechanism in the journal Leukemia in 2009. That too was challenging. "It's a new area so initially it was very difficult to get the work published. It was really out there," Professor Bebawy says. "Finally, the work is acknowledged. It's a huge team effort."

A team effort that was based on one eureka moment in the mind of one scientist. "That's why I encourage students to read outside their area to attend unrelated seminars," she says. "You may get an idea".

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There isn't usually a lot of news about transplants, but this is an interesting development:

SCIENTISTS FABRICATE RUDIMENTARY HUMAN LIVERS

By Gina Kolata

Researchers in Japan have used human stem cells to create tiny human livers lie those that arise early in fetal life. When the scientists TRANSPLANTED the rudimentary livers into mice, the little organs grew, made human liver proteins, and metabolized drugs as human livers do.

They and others caution that these are early days and this is still very much basic research. The liver buds, as they are called, did not turn into complete livers, and the method would have to be scaled up enormously to make enough replacement liver buds to treat a patient. Even then, the investigators say, they expect to replace only 30% of a patient's liver. What they are asking is more like a patch than a full liver.

But the promise, I a field that has seen a great deal of dashed hopes, is immense, medical experts said.

"This is a major breakthrough of monumental significance," said Dr. Hillel Tobias, director of transplantation at the New York University School of Medicine. Dr. Tobias is chairman of the American Liver Foundation's national medical advisory commitment.

"Very impressive," said Eric Lagasse of the University of Pittsburgh, who studies cell transplantation and liver disease. "It's novel and very exciting."

The study was published in the journal Nature.

Although human studies are years away, said Dr. Leonard Zon, director of the stem cell research program at Boston Children's Hospital, this to his knowledge, is the first time anyone has used human stem cells, created from human skin cells, to make a functioning solid organ, like a liver, as opposed to bone marrow, a jellylike organ.

Ever since they discovered how to get human stem cells -- first from embryos and now, more often, from skin cells -- researchers have dreamed of using the cells for replacement tissues and organs. The stem cells can turn into any type of human cell, and so it seemed logical to simply turn them into liver cells, for example, and add then to livers to fill in dead or damaged areas.

But those studies did not succeed. Liver cells did not take up residence in the liver; they did not develop blood supplies or signaling systems They were not a cure for disease.

Other researchers tried making livers or other organs by growing cells on scaffolds. But that did not work well either. Cells would fall off the scaffolds and die, and the result was never a functioning solid organ.

Researchers have made specialized human cells in petri dishes, but not three-dimensional structures, like a liver.

The investigators, led by Dr. Takanori Takebe of the Yokohama City University Graduate School of Medicine, begin with human skin cells, turning them into stem cells. By adding various stimulators ad drivers of cell growth they then turned the stem cells into human liver cells and began trying to make replacement livers.

They say they stumbled upon their solution When they grew the human liver cells in petri dishes along with blood vessel cells from human umbilical cords and human connective tissue, that mix of cells, to their surprise, spontaneously assembled itself into three-dimensional liver buds, resembling the liver at about five or six weeks of gestation in humans.

Then the researchers transplanted the liver buds into mice, putting them in two places: on the brain and into the abdomen. The brain site allowed them to watch the buds grow. The investigators covered the hole in each animal's skull with transparent plastic giving them a direct view of the developing liver buds. The buds grew and developed blood supplies, attaching themselves to the blood vessels of the mice.

The abdominal site allowed them to put more buds I -- 12 buds I each of two places in the abdomen, compared with one bud in the rain -- which let the investigators ask of the liver buds were functioning like human livers.

They were. They made human liver proteins ad also metabolized drugs that human livers -- but not mouse livers -- metabolize.

The approach makes sense, said Kenneth Zaret a professor of cellular and developmental biology at the University of Pennsylvania. His research helped establish that blood and connective tissue cells promote dramatic liver growth early in development ad help livers establish their own blood supply. On their own, without those other types of cells, liver cells do not develop or form organs.

"They were letting nature do its thing rather than trying to conceive of what the right signals might be," Dr. Zaret said. But, he said, the mice were studied for only a couple of months. He would lie to see what happens over a longer time.

"We don't know if the cells will grow out of control or will poop out," Dr Zaret said. Even if he liver buds never fulfill their clinical promise, they still could be enormously important for pharmaceutical research, Dr. Zon said. Drugs must be tested to see if they damage the liver, a major site of drug toxicity. Companies do this with liver cells taken from cadavers and grown in petri dishes But the liver buds could be a big improvement an offer a large supply of rudimentary livers for testing.

"That would be huge," Dr. Zon said. "It would open up lots of drugs in the pipeline and bring them in the clinic much more quickly."

Dr. Takebe ad his colleagues, though, are more focused on scaling up their process so they can think of trying to take it to the clinic, perhaps to treat babies and children whose livers have failed. Dr. Takebe estimates they would need hundreds of thousands, perhaps millions, of liver buds to replace 30% of the liver.

Dr. Tobias, the transplant surgeon, hopes they succeed.

"This is obviously the wave of the future," he said.

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Please read the following bearing in mind that timing is everything:

SCENTISTS URGE NARROWER RULES TO DEFINE CANCER

Reining In A Diagnosis

Panel Calls for Sweeping Changes in Detection and Treatment

By Tara Parker-Pope

A group of experts advising the nation's premier cancer research institution has recommended changing the definition of CANCER and eliminating the word from some common diagnoses as part of sweeping changes in the nation's approach to cancer detection and treatment. The recommendations, from a working group of the National Cancer Institute, were published in The Journal of the American Medical Association. They say, for instance, that some premalignant conditions like one that affects the breast called ductal carcinoma in situ, which many doctors agree is not cancer, should be renamed to exclude the word carcinoma so that patients are less frightened and less likely to seek what may be unneeded and potentially harmful treatments that can include the surgical removal of the breast.

The group, which includes some of the top scientists in cancer research, also suggested that many lesions detected during BREAST, PROSTATE, THYROID, LUNG and other cancer screenings should not be called cancer at all but should instead be reclassified as IDLE conditions, which stands for "indolent lesions of epithelial origin."

While it is clear that some of all of the changes may not happen for years, if at all, and that some cancer experts will profoundly disagree with the group's views, the report from such a prominent group of scientists who have the backing of the National Cancer Institute brings the discussion to a higher level and will most likely change the national conversation about cancer, its definition, its treatment and future research.

"We need a 21st-century definition of cancer instead of a 19th-century definition of cancer, which is what we've been using," said Dr. Otis W. Brawley, the chief medical officer for the American Cancer Society, who was not directly involved in the report.

The impetus behind the call for change is a growing concern among doctors, scientists ad patient advocates that hundreds of thousands of men and women are undergoing needless and sometimes disfiguring and harmful treatments for premalignant and cancerous lesions that are so slow growing they are unlikely to ever cause harm.

The advent of highly sensitive screening technology in recent years has increased the likelihood of finding these so-called incidentalomas -- the name given to incidental findings detected during medical scans that most likely would never cause a problem. However, once doctors and patients are aware a lesion exists, they typically feel compelled to biopsy, treat and remove it, often at great physical and psychological pain ad risk to the patient. The issue is often referred to as overdiagnosis, and the resulting unnecessary procedures to which patients are subjected are called overtreatment.

Cancer researchers warned about the risk of overdiagnosis and overtreatment as a result of new recommendations from a government panel that heavy smokers be given an annual CT scan While the policy change announced but not yet made final, has the potential to save 20,000 lives a year, some doctors warned about cumulative radiation risk of repeat scans as well as worries that broader use of the scans will lead to ore risky ad invasive medical procedures.

Officials at the National Cancer Institute say overdiagnosis is a major public health concern and a priority of the agency. "We're still having trouble convincing people that they things that get found as a consequence of mammography and P.S.A. Testing and other screening devices are not always malignancies in the classical sense that will kill you," said Dr. Harold E Varmus,, the Nobel Prize-winning director of the National Cancer Institute. "Just as the general public is catching up to this idea, there are scientists who are catching up, too."

One way to address the issue is to change the language used to describe lesions found through screening, said Dr. Laura J Esserman, the lead author of the report in The Journal of the America Medical Association and the director of the Carol Franc Buck Breast Care Center at the University of California, San Francisco. I the report, Dr Esserman a her colleagues said they would like to see a multidisciplinary panel convened to address the issue, led by pathologists, with input from surgeons, oncologists and radiologists, among others.

"Ductal carcinoma in situ is not cancer, so why are we calling it cancer?" said Dr. Esserman, who is a professor of surgery and radiology at the University of California, San Francisco.

Such proposals will not be universally embraced. Dr. Larry Norton, the medical director of the Evelyn H Lauder Breast Center at Memorial Sloan-Kettering Cancer Center, said THE LARGER PROBLEM IS THAT DOCTORS CANNOT TELL PATIETS WITH CERTAINTY WHICH CANCERS WILL OT PROGRESS AND WHICH CANCERS WILL KILL THEM, AND CHANGING TERINOLOGY DOES NOT SOLVE THAT PROLEM.

"Which cases of D.C.I.S. will turn into an aggressive cancer and which ones won't?" he said, referring to ductal carcinoma in situ. "I wish we new that. We don't have very accurate ways of looking at tissue and looking at tumors under the microscope and knowing with great certainty that it is a slow-growing cancer."

Dr. Norton, who was not part of the report, agreed that doctors do need to focus on better communication with patients about precancerous and cancerous conditions He said he often tells patients that even though ductal carcinoma in situ may look like cancer, it will not necessarily act like cancer -- just as someone who is "dressed like a criminal" is not actually a criminal until that person breaks the law.

"The terminology is just a descriptive term, and there's no question that has to be explained, "Dr. Norton said. "But you can't go back a change hundreds of years of literature by suddenly changing terminology."

But proponents of downgrading cancerous conditions with a simple name change say there is precedent for doing so. The report's authors note that in 1998, the World Health Organization changed the name of an early-stage urinary tract tumor, removing the word "carcinoma" and calling it "papillary urothelial neoplasia of low malignant potential." When a common Pap smear finding called "cervical intraepithelial neoplasia" was reclassified as a low-grade lesion rather than a malignancy, women were ore willing to submit to observation rather than demanding treatment, Dr Esserman said.

"Changing the language we use to diagnose various lesions is essential to give patients confidence that they don't have to aggressively treat every finding in a scan," she said. "The problem for the public is you hear the word cancer, and you think you will die unless you get treated. We should reserve this term 'cancer,' for those things that are highly likely to cause a problem."

The concern however is that since doctors do not yet have a clear way to tell the difference between benign or slow-growing tumors and aggressive diseases with many of these conditions, they treat everything as if it might become aggressive. As a result, doctors are finding and treating scores of seemingly pre-cancerous lesions and early-stage cancers -- like ductal carcinoma in situ, a condition called Barrett's esophagus, small thyroid tumors and early prostate cancer.

But even after years of aggressively treating those conditions, there has not been a commensurate reduction in invasive cancer, suggesting that overdiagnosis and overtreatment are occurring on a large scale. The National Cancer Institute working group also called for a greater focus on research to identify both benign and slow-growing tumors and aggressive diseases, including the creating of patient registries to learn more about lesions that appear unlikely to become cancer.

Some of that research is already under way at the National Cancer Institute.. Since becoming director of the institute three years ago, Dr. Varmus has set up a list of "provocative questions" aimed at encouraging scientists to focus on critical areas including the issue of overdiagnosis and molecular tests to distinguish between slow-growing and aggressive tumors.

Another National Cancer Institute program, the Barrett's Esophagus Translational Research Network, or Betrnet, is focused on changes in the esophageal lining that for years have been viewed as a precursor to esophageal cancer. Although patients with Barrett's are regularly screened and sometimes treated by burning off the esophageal lining data now increasingly suggest that most of the time, Barrett's is benign and probably does not need to be treated at all. Researchers from various academic centers are now working together and pooling tissue samples to spur research that will determine when Barrett's is most likely to become cancerous.

"Our investigators are not just looking for ways to detect cancer early, they are thinking about this question of when you find a cancer, what are the factors that might determine how aggressively it will behave" Dr. Varmus said. "This is a long way from the thinking 20 years ago, when you found a cancer cell and felt you had a tremendous risk of dying."

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Until next month ..

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And if you have any thoughts of how this newsletter could be improved, please email me directly, at Elaine@elainejesmer.com.

Elaine Jesmer

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