Chemotalk Newsletter, Vol. 42: October 1, 2011
VIRUS SENT ON A SEEK-AND-DESTROY MISSION AGAINST CANCER
By Howard Lovy
Drug-delivery technology is all about selectively killing disease while leaving healthy cells alone. Turns out, you can engineer a virus to do the same thing, according to a report in Technology Review. In an early-stage trial, 23 patients with METASTATIC CANCERS were injected with a new type of cancer-killing virus. Half of the patients saw their tumors stop growing, and a tumor shrank in one patient. The results appear in the journal Nature.
The study seems to confirm viruses can selectively target cancer cells. The study was funded by Jennerex, a San Francisco biotech, which set out to find a virus that does not need to be injected directly into tumors, but can travel through the bloodstream on a seek-and-destroy mission. The result was JX-594, which is a strain of the vaccinia virus armed with GM-CSF, which triggers an immune attack against cancer cells. They also added a marker protein to track the virus's replication. The effect, according to Jennerex CEO David Kirn, was "a product that destroys tumors by multiple, complementary mechanisms."
The technology is being tested in larger trials and recently completed a successful trial for LIVER CANCER.
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Some of the following piece is pretty technical, but you'll still get the gist if you read through. It's pretty exciting for anyone with advanced breast cancer:
DRUG SHOWS SURVIVAL BENEFITS IN PHASE 2 BREAST CANCER TRIAL
Syndax Pharmaceuticals, Inc, a clinical-stage epigenetics oncology company, announced today that ENCORE 301, a randomized, placebo-controlled phase 2 study of exemestane with and without entinostat hit its primary endpoint of an improvement in progression-free survival (PFS). The study showed that patients who received entinostat, a novel, oral small molecule inhibitor of class I histone deacetylases, with the hormone therapy exemestane, lived longer without their disease getting worse than people who received exemestane alone. Safety and efficacy results from the trial will be presented in a poster and an oral presentation at the American Society of Clinical Oncology (ASCO) Breast Cancer Symposium 2011 in San Francisco, CA.
"Entinostat combined with exemestane prolonged progression-free survival, reducing the risk of disease progression by 27% and showing an improvement in overall survival for post-menopausal women with estrogen-receptor positive METASTATIC BREAST CANCER," said Denise A. Yardley, MD, breast program leader, senior investigator at the Sarah Cannon Research Institute and principal investigator of the study. "Furthermore, in a subset of patients evaluated for a pharmacodynamic measure of entinostat's effect, we demonstrated for the first time with this class of agents evidence of an association of protein lysine hyperacetylation with clinical outcome. I am extremely excited to be able to work with Syndax to validate the findings from this randomized phase 2 blinded, placebo-controlled trial with the development of a larger phase 3 confirmatory trial in hormone receptor-positive advanced breast cancer patients."
ENCORE 301 (ENtinostat Combinations Overcoming REsistance) was a multicenter, randomized, double-blind, placebo-controlled, phase 2 study of exemestane with and without entinostat in 130 postmenopausal women with locally recurrent or metastatic estrogen receptor-positive breast cancer, progressing on treatment with the non-steroidal aromatase inhibitors anastrozole or letrozole. The primary endpoint of the study was progression-free survival. Other endpoints included objective response rate (ORR), clinical benefit rate (CBR), overall survival (OS) and safety and tolerability.
All patients had received prior hormonal therapy (1 prior line 42%; >1 prior line 58%), and 33% had received prior chemotherapy in the advanced breast cancer setting. The results of this study with well-balanced arms included the following:
* In the intent-to-treat population progression-free survival was significantly longer (defined prospectively as 1-sided p <0.10) with exemestane plus entinostat than with exemestane plus placebo (4.28 versus 2.27 months, respectively; hazard ratio (HR) = 0.73; p=0.06);
* In the intent-to-treat population, with a median follow-up of 18 months, overall survival was significantly longer with exemestane plus entinostat than with exemestane plus placebo (26.94 versus 20.33 months, respectively; hazard ratio (HR) = 0.56; p=0.027);
* In the subset of entinostat patients with protein acetylation data (n=27), median PFS increased to over six months in the patients exhibiting protein lysine hyperacetylation; * Entinostat combined with exemestane was well tolerated with the most frequent adverse events (AE) consisting of fatigue, gastrointestinal disturbances and hematologic abnormalities; and
* Serious AE rate was similar for exemestane plus entinostat (13%) and exemestane plus placebo (12%).
"Delaying disease progression and improving survival, combined with an attractive safety profile, makes entinostat and exemestane an exciting option for patients with advanced ER-positive breast cancer," said Kathy D. Miller, MD, associate professor at Indiana University and trial investigator. "Hormone therapy remains the mainstay of treatment for patients with hormone-sensitive disease. These clinical results provide hope to clinicians and patients that we may be able to delay resistance and increase the time to disease progression, maintaining women longer on hormone-based therapy with fewer side effects than chemotherapy."
"Based on the positive results from ENCORE 301 and the enthusiasm of the breast cancer community, we plan to enroll the first patient into a global, pivotal phase 3 study in early 2012," said Joanna Horobin, MD, president and chief executive officer of Syndax. "While epigenetic drugs are approved for hematologic malignancies, if entinostat proves successful in this breast cancer setting, this would be the first epigenetic therapy to benefit patients with solid tumors, representing not only an important contribution to the treatment of breast cancer but a significant commercial opportunity."
Breast Cancer and Hormone Therapy
Approximately 230,000 new cases of invasive breast cancer are diagnosed in women annually in the United States and there are approximately 150,000 women living with metastatic breast cancer (MBC). Over 70 percent of women with breast cancer have estrogen receptor-positive (ER+) breast cancer. The most effective cancer treatments target the underlying biology and in breast cancer the most common oncogenic driver is estrogen receptor signaling. Blocking estrogen activity with aromatase inhibitors represents an effective treatment for most ER+ MBC patients, however acquired drug resistance to aromatase inhibitors leads to disease progression, ultimately requiring less effective, more toxic chemotherapies.(1) Delaying resistance and disease progression represents a significant unmet need that could prolong survival while decreasing health care costs associated with chemotherapy and hospitalization.
Syndax's lead product entinostat is a novel, oral small molecule inhibitor of class I histone deacetylases, key enzymes that alter the structure of chromatin to control gene expression. Entinostat is differentiated from other members of the class through its unique selectivity profile, pharmacokinetic properties and safety profile. Entinostat has been studied in more than 600 cancer patients where objective tumor responses have been observed in both solid and hematologic malignancies.
Breast cancer animal models demonstrated that resistance to aromatase inhibitors occurs through up-regulation of growth factor signaling pathways and down-regulation of estrogen receptor alpha. Entinostat effectively down-regulates growth factor signaling in breast cancer cells where these pathways are active. Entinostat also up-regulates the expression of ER in breast cancer cells which have negligible or undetectable levels of estrogen receptor. The ability to target multiple mechanisms of resistance establishes entinostat as a promising candidate for preventing and overcoming aromatase inhibitor resistance through epigenetic modulation. In pre-clinical testing entinostat induced tumor regression when combined with aromatase inhibitors after the development of aromatase inhibitor resistance.
Additional phase 2 studies with entinostat have demonstrated promising results in combination with the EGFR-TKI erlotinb (ENCORE 401) in non-small cell lung cancer and as a single agent in Hodgkin's lymphoma (ENGAGE 501). Results from the ENCORE clinical program provide the basis for moving entinostat into pivotal, phase 3 testing in metastatic breast and lung cancer settings.
Syndax Pharmaceuticals, Inc. is a Waltham, MA-based, late-stage, oncology-focused pharmaceutical company.
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CUBA ANNOUNCES LAUNCH OF LUNG CANCER VACCINE
By Erica Teichert
Cuba has commenced sales of the world's first therapeutic LUNG CANCER vaccine this week after 25 years of research at the Center of Molecular Immunology in Havana, according to Xinhua.
"The drug could turn the cancer into a manageable, chronic disease by generating antibodies against the proteins which triggered the uncontrolled cell proliferation," said Gisela Gonzalez, head researcher of the vaccine, as quoted by Xinhua. The vaccine, CimaVax-EGF, is based on "a protein we all have when cancer is uncontrolled," and will be used for stage three and stage four lung cancer patients who have not responded to traditional chemotherapy and radiotherapy treatments, Gonzalez said. For now, the vaccine remains on Cuba alone, distributed free of charge in hospitals. It will be studied for its effects in other cancer types including PROSTATE, UTERINE and BREAST CANCERS.
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I found this piece in my files. It's almost a year old, but I think it holds up to the test of time:
IN ILLNESS, OLD DREAM IS REALIZED
By Dana Jennings
When I was a boy, I ached to be a scientist. I was the kind of kid who needed to now why and how -- right now! -- not to mention who, what, where and when.
How can there be lightening but no rain? Why do eels wriggle in the skillet when you're frying them up? Why do dirty socks smell like corn hips? The summer porch was my lab, where I wrote and drew (and dreamed), dissected mummified goldfinches and fiddled with my chemistry set, hoping against hope that something interesting would happen.
After I learned two years ago that I had an aggressive Stage 3 PROSTATE CANCER, I rediscovered my kid scientist. And it was that inquisitive kid who nudged me toward scrutinizing my life with cancer, to write columns and blog posts:
Why did I get cancer? Will it kill me? Who am I now that I have it, and who will I be if I survive it?
Yes, cancer raises many more questions than can possibly be answered. But that realization pricked the curiosity of my kid scientist. I was stirred by the idea of studying myself, determined to treat myself as if I were a cancer experiment of one.
That doesn't mean I dallied with the freakish "cures" offered by gonzo medicine: thanks, pal, but I'll pass on the monkey glands today. It just meant that I planned to pay hard attention, using all five of my senses. If I had to have cancer, I wanted to see what it could teach me.
When we're seriously ill, we deal with a set of institutions that have -- to put it mildly -- different priorities from ours.
To health insurers we're gross and inconvenient red marks against their bottom lines. They'd prefer that we meekly mill and low in the cattleyards of the medical-institutional complex, doing what we're told, keeping our mouths shut and not causing too much trouble.
To doctors and nurses, we're part of their caseload. Most of them show compassion toward their patients, but we also have to understand that we're just one component on their daily assembly line of hearts and souls. Just call me Prostate No. 436B.
And to the medical students who rustle and jostle into the room right about daybreak like middle schoolers wearing stethoscopes, we're an exhibit: "Please note that Mr. Jennings also wears an ostomy pouch because he has no colon." We're one of the morning's lessons. If we're unlucky enough to be "unusual," we might even be promoted to being a quiz or a test or, God forbid, a thesis.
No matter how awful we feel we can't capitulate to our cancers, can't cede control of these unexpected experiments in which our lives hang in the balance. By claiming ownership of my cancer -- rather than sighing and saying that it was "just one of those things" -- I demanded to learn what it could teach me. I wasn't just meat for the scalpel, wanton cells sentenced to death by radiation, testosterone throttled by hormone therapy. I was subject, student, observer -=- the lead scientist on this project, if you will.
Playing host to a rapacious cancer was much more than being sick" it was a multisememster, multidiciplinary seminar, enough for at least a backelor's degree in cancer studies. My inner kid scientist and I were tested on oncology, urology, hematology and pain management; radiology, hormonology imaging technology and anesthesiology; glycoproteins, genetic probability, pharmacology (and psychopharmacology).
Then there were surgical options, radiation, hormone therapy and drawing your own blood or a rainy day (a one-day bonus lab); pulmonology, fatigue studies, depression and psycho-oncology; impotence, incontinence, male and female sexuality and, for extra credit, stalking the elusive libido. (If I've forgotten any -ologies, well, my apologies.)
A heavy load, this experiment of one, but a real education that my kid scientist couldn't have imagined more than 40 years ago. And we'll tell you one more thing: We don't plan to do any postgrad work anytime soon.
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NEW DRUG FOR BASAL CELL CARCINOMA SENT TO FDA
Genentech has submitted a New Drug Application for vismodegib to the U.S. Food and Drug Administration (FDA) for the treatment of people with advanced BASAL CELL CARCINOMA (BCC) for whom surgery is considered inappropriate. Vismodegib is an investigational, oral, targeted medicine designed to selectively inhibit signaling in the Hedgehog pathway, which is implicated in more than 90 percent of BCC cases. BCC is the most common type of skin cancer, which is generally considered curable by surgery. However, when it advances, BCC can cause disfiguring and debilitating effects and can ultimately be life-threatening.
This submission to the FDA is based on results from the pivotal ERIVANCE BCC study that evaluated vismodegib in people with advanced BCC. The trial showed vismodegib substantially shrank tumors or healed visible lesions (overall response rate, or ORR) in 43 percent of patients with locally advanced BCC (laBCC) and 30 percent of patients with metastatic BCC (mBCC), as assessed by independent review, the primary endpoint of the study.
The median duration of progression-free survival (PFS) by independent review for both metastatic and locally advanced BCC patients was 9.5 months.
The most common drug-related adverse events were muscle spasms, hair loss, altered taste sensation, weight loss, fatigue, nausea, decreased appetite and diarrhea. Serious adverse events (SAEs) were observed in 26 patients (25 percent). Four patients (4 percent) had SAEs that were considered to be related to vismodegib, including one case each of: blocked bile flow from the liver (cholestasis), dehydration with loss of consciousness (syncope), pneumonia accompanied by an inability of the heart to pump enough blood (cardiac failure) and a sudden arterial blockage in the lung (pulmonary embolism). Fatal events were reported in seven patients (7 percent); none were considered by investigators to be related to vismodegib. In all cases, patients had other pre-existing diseases or symptoms that were related to their presumed cause of death.
In order to provide people with advanced BCC who are appropriate candidates access to vismodegib while Genentech discusses next steps with the FDA, the company is conducting an expanded patient access study in the United States. For more information, patients and doctors can contact the Genentech clinical trial call center at 888-662-6728 or visit http://www.clinicaltrials.gov.
About Basal Cell Carcinoma and the Hedgehog Pathway
According to the American Cancer Society, BCC accounts for approximately 80 percent of all diagnosed skin cancers. In the majority of cases, the disease is generally considered curable if the cancer is restricted to a small area of the skin. However, in a very small group of people, if the disease is left untreated or recurs after surgery, it becomes locally advanced, and the cancer may invade further into surrounding tissues such as sensory organs (ears, nose and eyes), bones or other tissues. In a small proportion of patients (estimated at less than one percent of those affected), BCC can metastasize, spreading to other parts of the body. Currently, there are limited treatment options for advanced BCC with no standard of care.
The Hedgehog signaling pathway plays an important role in regulating proper growth and development in the early stages of life and becomes less active in adults. In addition to BCC, mutations in the pathway that reactivate Hedgehog signaling are seen in several types of cancer.
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This is from the "We Can Dream..." department. On the other hand, if it works in humans, it's as close to curing cancer as it gets:
FROM A POISONOUS CROCUS, COMES AN ANTI-CANCER SMART BOMB
By Howard Lovy The autumn crocus is a beautiful but deadly flower. There is no antidote to colchine, the arsenic-like toxin it releases. Nonetheless, there is reason for the British to try to save this native endangered plant, because it just might help cure many kinds of CANCERS.
While colchicine, the drug based on the autumn crocus, is already put to use fighting gout, a modified version of it is being touted as a smart bomb that detonates only when it comes into contact with tumor cells, leaving healthy ones alone.
Scientists are claiming that the drug, known as ICT2588, is effective against all forms of solid tumors. "We have found a way to harness colchicine's power so that it is harmless to healthy tissue, but still toxic to tumor blood vessels," Kevin Adams, of Bradford University's Institute for Cancer Therapeutics, told The Irish Times.
ICT2588 destroyed breast, bowel, lung and prostate cancer tumors in mice, surprising even the researchers when more than half of the mice went into total remission after one injection, and it slowed tumor growth among the rest. It works only when it comes into contact with MMT1, an enzyme used by tumors to invade surrounding tissue. ICT2588 prevents formation of new blood vessels to feed the tumor, essentially starving it.
Medical News Today reports that the researchers are negotiating with a sponsor for the money they need to take the compound to human trials, planned to take place at St. James' University Hospital in Leeds.
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STUDY CONCLUDES COMMONLY USED PAIN PILLS INCREASE KIDNEY CANCER RISK
Brigham and Women's Hospital*
Pain medicines routinely taken by millions of people to ease headaches and joint pain may also increase the risk of KIDNEY CANCER, researchers said.
People who regularly used ibuprofen, sold by Johnson & Johnson (JNJ) as Motrin and Pfizer Inc. (PFE) as Advil, or naproxen, sold by Bayer AG (BAYN) as Aleve, were 51% more likely to develop kidney cancer than those who didn¹t rely on the pills, according to a study published in Archives of Internal Medicine. There wasn¹t an increased risk from aspirin or acetaminophen, the main ingredient in J&J¹s Tylenol.
* This hospital was added as a tag to the headline of this story, but at no point was the connection made. I'm assuming they produced the study.
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