Chemotalk Newsletter

Good morning!

There's a real sense of immediacy connected to the topic of cancer treatment.  When lives are literally on the line, treatment takes center stage.  But what causes cancer, is a question that deserves more attention than I've been giving it in this newsletter.  Here's one story designed to start "trending" (yes, it's an adverb now) in another direction.  Looks like China could use an Erin Brockovich:

CHINA CANCER VILLAGE TESTS REACH OF LAW AGAINST POLUTION

    XIAOXIN, China (Reuters) - Nothing in Wu Wenyong's rural childhood hinted he would end up on a hospital bed aged 15, battling two kinds of CANCER.  Born to poor farmers in Xiaoxin, a dusty village of low brick houses in southwestern Yunnan province, he paddled in the Nanpan River as a child and later helped his parents tend rice.

    About 3 km (two miles) from Wu's home stands a three-storey high hill of chromium slag produced from the Yunnan Luliang Peace Technology Company. The runoff from chromium-6, listed as a carcinogen by the World Health Organisation, seeped into the Nanpan, turning its waters yellow.

    And the toxic water and earth that Wu's family blames for his condition have become a battleground over how far China will bend to letting courts punish pollution.  The chromium hill is a rallying point for a coalition of environmental advocacy groups, who have filed a public interest lawsuit for residents of Xiaoxin and nearby Xinglong in a special environment court.

    Last September, Wu's face ballooned and tumor-like growths developed on his neck. He was diagnosed with THYOMA, cancer of the thymus gland in the chest, and with LEUKEMIA.

    "The pollution is quite terrible. I've heard stories of cattle dying," Wu said, from his hospital bed in Kunming, the capital of Yunnan. "I've seen the water in the river and it's all yellow. I've never drunk the water."

    Beset by growing public alarm and protests about pollution, China's leaders have reached for a remedy they have otherwise shown little appetite for: letting the courts decide. Those courts come under the control of the ruling Communist Party, but environmental campaigners spot a welcome, if narrow opening.

    In a country where non-governmental organizations have long been treated with suspicion by authorities, collective litigation by organizations with no government backing is breaking new ground in the environment courts. The groups want the privately owned company to establish a 10 million yuan ($1.6 million) compensation fund for an environmental clean-up.

    "This is a significant case," said Qin Tianbao, a professor of environmental law at Wuhan University, uninvolved in the case. "In the past, lawsuits were only launched by agencies with semi-official backing. If it is possible that an organization with absolutely no government backing can bring about a public interest litigation, then it certainly is a good thing."

    The Yunnan Luliang Peace Technology Co. was established in 2003, according to its website. It makes chromium, a metal used in stainless steel, paints, plastic and dyes, and sodium dichromate, used for the tanning of leather.

    Both are highly carcinogenic metals.

    The company declined Reuters' request for an interview.

    Polluting factories have been relocated from urban areas to the countryside, home to half of China's population. Local officials rely on these industries to generate tax revenues.  "Why was the factory built here and not Beijing and Shanghai? Because in Beijing and Shanghai, there are people watching," said Chang Shichen, 47, a villager from Xinglong.

    The lawsuit had been due to go to trial in the city of Qujing last November, but was delayed until February to give advocates more time to assess the ecological damage, said Li Bo, director of Friends of Nature, one of the groups involved.

    Environmental groups dispute local authorities' assertion that the water is now safe.

    "There is no problem with the village's water now, although I'm not sure about the specific circumstances," Ji Honghua, an official with the Qujing Municipal Environmental Protection Bureau, said by telephone.

    In the two villages, which are surrounded by an industrial park, residents drink either bottled water or water supplied from a small river and later filtered.

    The local government gave Wenyong's father, Wu Shuliang, 1,000 yuan* after he told officials about his son's plight. He borrowed 50,000 yuan for his son's CHEMOTHERAPY -- and family members say there is no health insurance to reclaim the money.  "All I want is for the government to give us an answer about the pollution," said Wenyong.  His hair has fallen out from chemotherapy and he weighs 32 kg (70 pounds), almost 10 kg lighter than before his illness.  Wenyong's doctor, a woman surnamed Li, said her patient in any case needs two to three years of follow-up treatment.

    Last year, the environmentalist Li learned from a media report that 5,000 tonnes of chromium-6 had been dumped outside a district of Qujing. He investigated and found 140,000 tonnes had been buried in the nearby villages of Xiaoxin and Xinglong.

    "Many villagers didn't know what chromium is, they thought it was soil, so they'll dig up the chromium to pave roads. "Others will use it to build the foundation of their homes," he said. "They work barefooted in the fields. Some of their feet would start to rot and they would never understand why."

HIGH EXPOSURE

    The chromium-6 levels in the water were 200 times above the permissible limits, Ma Tianjie of Greenpeace in China said after an independent investigation was conducted.

    Enforcement of laws regulating the disposal of chromium is poor. Greenpeace's Ma estimates there are 1 million tonnes of chromium-6 dumped across China that still has not been disposed of, based on environment ministry data.

    Virtually every resident of the villages knew of someone who contracted cancer after the industrial park was set up about seven years ago. No epidemiological studies have been conducted.

    Studies have shown that exposure to chromium-6 causes leukemia and cancer of the stomach, liver and breast.  "It is one of the worst chemicals to get in drinking water," Max Costa, chairman of the department of environmental medicine at New York University, said in emailed comments.

    Wu's family needs no convincing about what is to blame.  "Our plot of farmland was just next to the chromium slag," said the elder Wu. "They even dug a drain next to our land for the runoff."

    In September, the local government arrested five people for the dumping and ordered the company to halt production of chromium and sodium dichromate.  The hill is now covered by metal slabs. Guards monitor the company around the clock to ensure production has stopped and detoxification will be completed in August, Ji from the Qujing environmental bureau said.

    Li recruited lawyers, academics and other NGOs to look into the feasibility of filing a lawsuit and the team named the Qujing Environmental Protection bureau as a co-plaintiff,  Two weeks after their case was accepted by the Qujing court, the central government's Civil Law Draft Amendment Office sought Li's views on amendments to draft legislation.

    An official told him the government was considering letting "social organizations" bring lawsuits about pollution and food safety.  Although "social organizations" have not been defined, new laws could lead to more "public interest" litigation and allow ordinary people to join forces to defend their interests.

    Li said he was "cautiously optimistic" about prospects for victory in the Qujing case -- which he said he had raised in his discussions with the government.  "If this has already happened, that an environmental organization with a status like ours could successfully file a public interest lawsuit, not including us in future interpretations of the amendments to the civil law, will be something that is unjustified," he told the official.

    But without an independent judiciary, the environment courts will continue to avoid handling sensitive cases, said Zhang Jingjing, a lawyer involved in many pollution causes.  "Our circle of lawyers has a saying: in China, the big cases are about politics, the mid-sized cases are about influence and only the small cases deal with law," Zhang said.

*($1 = 6.3066 Chinese yuan)

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BREAST CANCER VACCINE SET FOR LARGE-SCALE TESTING

    A BREAST CANCER cancer vaccine spearheaded by the military is due to begin large-scale clinical trials early this year in preparation for FDA submission, according to a recent report by the American Forces Press Service.

    Galena Biopharma ($GALE) has rights to the therapeutic vaccine, which combines the E-75 peptide with the HER2/neu protein and an immune system stimulant, and was developed by the Cancer Vaccine Development Program at the San Antonio Military Medical Center. The vaccine is designed to spur immune attacks on HER2-driven cancers, and Galena's upcoming trials for the treatment aim to combat recurrence of breast cancer.

    Outcomes from earlier phase testing in disease-free cancer survivors at risk of recurrence were promising: "We cut recurrence in half," said center director and principal investigator, Army Col. Dr. George Peoples. The new studies in 700 to 1,000 patients are expected to take about 5 years to complete, with the endpoint being recurrence after three years.

    Galena acquired additional patent rights to the E-75 vaccine, which it has dubbed NeuVax, from the military in July 2011. The company, which is based in Portland, OR, announced it is working with Genentech on a mid-size trial studying NeuVax in combination with Genentech's blockbuster breast cancer drug Herceptin in 300 breast cancer patients currently not eligible for Herceptin therapy.

    Dr. Peoples said the center also has conducted a successful small trial of the vaccine and Herceptin together?in which?the recurrence rate was zero. In addition, the center has completed a trial with the vaccine in prostate cancer survivors. Prostate cancer cells also express the HER2 protein.

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 I'm an admitted research wonk.  The following makes me smile:

RESEARCHERS DECODE SOME KIDNEY CANCER SECRETS

    Knowing your enemy helps to defeat it. Researchers at the Van Andel Research Institute in Michigan kept that in mind with two separate studies that have helped unlock some secrets of certain KIDNEY CANCERS.

    Learning a cancer's mode of operation is crucial to developing a way to defeat it. Understanding more of a cancer's "moving parts," for example, can reveal new drug targets that scientists may not have known about previously.

    The first study compared the aggressive kidney cancer known as Type 2 papillary renal cell carcinoma, or PRCC2, which has no known treatment that works, with clear cell renal cell carcinoma, or CCRCC, a subtype and far more common form of kidney cancer that shrinks away from drugs targeting vascular endothelial growth factor. While the cancers are different, scientists believe that hereditary PRCC2 and CCRCC share similar pathway deregulation. They found that deregulation of the KEAP1-NRF2 signaling pathway does indeed distinguish PRCC2 from CCRCC, but the process links hereditary and sporadic PRCC2. Scientists from Singapore, France and the U.S., including groups such as the Cleveland Clinic, participated.

    CCRCC also took the stage for the second study. Researchers collaborating with peers in Singapore wanted to identify genes that factor into the cancer's progression. By integrating gene expression profiling and RNAi screening data, they found that genes related to cell-cycling, such as PLK1, seem to control disease aggressiveness. They also discovered that PLK1 is a potential target in fighting CCRCC.

The studies are published in Cancer Cell and Cancer Research, respectively.

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And...

PREVIOUSLY UNCONNECTED MOLECULAR NETWORKS CONSPIRE TO PROMOTE CANCER

An inflammation-promoting protein triggers deactivation of a tumor-suppressor that usually blocks CANCER formation via the NOTCH signaling pathway, a team of researchers led by scientists at The University of Texas MD Anderson Cancer Center reports today in Molecular Cell.

    Working in LIVER CANCER cell lines, the team discovered a mechanism by which tumor necrosis factor alpha (TNF$B&A(B) stimulates tumor formation, said senior author Mien-Chie Hung, Ph.D., professor and chair of MD Anderson's Department of Molecular and Cellular Oncology. Hung also is MD Anderson's vice president for basic research.

    "We've discovered cross-talk between the TNF$B&A(B inflammation and NOTCH signaling pathways, which had been known to separately promote cancer development and growth," Hung said. Liver cancer is one of several cancers, including pancreatic and breast, associated with inflammation.

    Their findings have potential implications for a new class of anti-cancer drugs currently in clinical trials. "Pharmaceutical companies are developing NOTCH inhibitors," Hung said. "TNF$B&A(B now presents a potential resistance mechanism that activates NOTCH signaling in a non-traditional way."

Pathways also unite in COLON, LUNG, and PROSTATE cancers.

    "In addition, co-activation of these two pathways was also observed in colon, lung and prostate cancers, suggesting that the cross-talk between these two pathways may be more generally relevant," Hung said.  However, TNF$B&A(B also presents an opportunity to personalize therapy, Hung said. The presence of TNF$B&A(B or a separate protein that it activates called IKK alpha may serve as useful biomarkers to guide treatment.

    "If a patient has only NOTCH activated, then the NOTCH inhibitor alone might work. But if TNF$B&A(B or IKK$B&A(B are also activated, then the NOTCH inhibitor alone might not work very well and combination therapy would be warranted," Hung said.  "We'll try this in an animal model and then go to clinical trial if it holds up," Hung said.

A path from inflammation to liver cancer

    In a series of experiments, Hung and colleagues connected the following molecular cascade:

    TNF$B&A(B, a proinflammatory cytokine, signals through a cell's membrane, activating IKK$B&A(B, a protein kinase that regulates other proteins by attaching phosphate groups (one phosphate atom, four oxygen atoms) to them. IKK$B&A(B moves into the cell nucleus, where it phosphorylatesFOXA2, a transcription factor that normally fires up the tumor suppressor NUMB. NUMB usually blocks a protein called NICD, the activated portion of NOTCH1 that slips into the cell nucleus to activate genes that convert the normal cell to a malignant one. But when FOXA2 is phosphorylated, it does not activate NUMB. With NUMB disabled, NOTCH1 is activated.

New understanding, new targets for cancer therapy

    In liver cancer (hepatocellular carcinoma) tumors, IKK$B&A(B, the phosphorylated version of FOXA2 and NOTCH1 are expressed more heavily than in normal liver tissue. Expression of all three is correlated in liver cancer tumors, the team found.

    The authors conclude that identifying the link between TNF$B&A(B and NOTCH1 pathways provides a new starting point for understanding the molecular basis for TNF$B&A(B-related tumor growth and for identifying new targets for cancer therapy.  Finding ways to inhibit FOXA2 phosphorylation or to activate NUMB would provide new options for treating and perhaps preventing cancer, Hung said.

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CANCER SURGERY IN PATIENTS WITH DIABETES

    People with diabetes are at increased risk for developing some CANCERS and are more likely than nondiabetecs to die of cancer.  Now a study reports that they also have a higher risk of dying in the weeks just after cancer surgery.

    The analysis of 15 earlier studies encompassed almost 60,000 patients, both with and without diabetes, who underwent surgery for cancers of the COLON, ESOPHAGUS, LIVER, LUNG, STOMACH, PANCREAS and PROSTATE.  It found that the patients with pre-existing diabetes were 50% more likely than nondiabetic patients to die within a month of surgery, regardless of the type of cancer.

    The patients in the studies had both types of diaetes, though Type 2 is more common.

    Their higher death rate may have resulted from problems associated with the chronic illness, like a greater risk of infections and heart disease, said Hsin-Chieh Yeh, assistant professor of medicine and epidemiology at Johns Hopkins School of Medicine and an author of the paper, published in the April issue of Diabetes Care.

    "The implication of this is that diabetes care is important on top of the cancer care," Dr. Yeh said.  "When patients are diagnosed with cancer, the patient and the family and the physician think, 'This is serious -- we have to take care of the cancer part first.'  And sometimes they forget about the diabetes they have."

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FDA APPROVES BTG'S DRUG FOR CHEMOTHERAPY TOXICITY

    U.S. health regulators gave the nod to a drug from British specialty drugmaker BTG Plc that helps CANCER patients get rid of toxic levels of a CHEMOTHERAPY treatment.  The drug, called Voraxaze, helps eliminate methotrexate in patients whose kidney function has been compromised by treatment with high doses of the chemotherapy agent.

    Methotrexate is normally eliminated from the body by the kidneys, but prolonged high doses of the drug used to treat cancer can result in kidney failure.  BTG's injectable treatment can quickly break down the chemotherapy medicine and allow the body to expel it.

    The Food and Drug Administration granted Voraxaze orphan drug status, meant for rare diseases or conditions that affect a very small portion of the population. As incentive for companies to develop such drugs, the orphan designation comes with seven years of marketing exclusivity before a rival medicine could be approved.

    Methotrexate is used to treat BREAST, BONE and LUNG CANCER, as well as LEUKEMIA. In much lower doses, it is commonly used to treat RHEUMATOID ARTHRITIS and other autoimmune diseases.

    Prolonged exposure to the chemotherapy treatment can cause kidney and liver damage, skin rash and severe mouth sores, damage to the lining of the intestines, and death because of low blood counts, said Richard Pazdur, the head of the FDA's cancer drugs division.  "Voraxaze is an important new treatment option for cancer patients aimed at preventing these toxicities associated with sustained high levels of methotrexate," Pazdur said in a statement.

    In a clinical trial of 22 patients, Voraxaze eliminated 95 percent of methotrexate from their blood. For 10 of the patients, the methotrexate fell to a low level within 15 minutes and stayed that way for eight days, the FDA said.  Common side effects included low blood pressure, headaches, nausea and vomiting.

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TRACE ELEMENTS AND PANCREATIC CANCER RISK

    A new study has found that high bodily levels of the trace elements nickel and selenium may be associated with reduced risk for PANCREATIC CANCER, and that high levels of arsenic, cadmium and lead may increase the risk.

    The study, published in the journal Gut, included 118 pancreatic cancer patients and 399 patients with other diagnoses at several hospitals in Spain.  Rearchers analyzed toenail samples with plasma mass spectrometry, a highly sensitive technique for detecting trace elements.

    After controlling for age, sex, smoking, diabetes and other factors, the scientists found that the subjects with the highest levels of arsenic were at twice the risk for pancreatic cancer, compared with those with the lowest concentrations.  Those with high levels of cadmium were at three times the risk for pancreatic cancer, while those with the highest levels of lead were at six times the risk.

    Those with the highest levels of nickel and selenium, on the other hand, were at significantly lower risk for pancreatic cancer.

    Dr. Nuria Malats, an epidemiologist at the Spanish National Cancer Research Center and the senior author of the new study, said that it was the first to provide these kinds of results with trace elements, and that it did not mean that people should take dietary supplements.

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NOVEL BRAIN TUMOR VACCINE ACTS LIKE BLOODHOUND TO LOCATE CANCER CELLS

    A national clinical trial testing the efficacy of a novel BRAIN TUMOR vaccine has begun at Wake Forest Baptist Medical Center. The vaccine will be tested in patients with newly diagnosed glioblastoma multiforme (GBM), the most aggressive and highest grade malignant glioma.  A minimum of 25 patients will be treated in this randomized, placebo-controlled phase II clinical trial of ICT-107. A total of 20 sites across the country are participating in the trial to test the safety and efficacy of this novel cancer vaccine.

    All patients enrolled in the study will receive the current standard treatment for GBM, which includes surgery followed by radiation and chemotherapy. Two thirds of the participants will then also get the experimental vaccine treatment, which will be administered in the post radiation phase of treatment, while the others will get a "dummy," or placebo vaccine in addition to standard therapy.

    "This vaccine is for newly-diagnosed patients," said Glenn Lesser, M.D., a professor of internal medicine, hematology-oncology, at Wake Forest Baptist and principal investigator for the study.

    The approach with this particular vaccine is unique, Lesser added, because it is targeting the antigens or proteins that are present on glioma stem cells, whereas other treatment approaches mostly target differentiated tumor cells.  "The antigens used in this vaccine target the tumor stem cells -- the handful of cells that keep the tumor alive and dividing. Most of the cells we kill with standard treatment are likely not the ones driving the tumor growth. If the stem cells aren't targeted, they keep generating more tumors."

    According to the biotechnology company that is conducting the trial, the Phase I clinical study of ICT-107 in GBM involved 16 newly-diagnosed patients who received the vaccine in addition to standard therapy -- surgery, radiation and chemotherapy. Those patients demonstrated a one-year overall survival of 100 percent and a two-year survival of 80 percent. Although only a small number of patients were treated, these results compare favorably with historical 61percent one-year and 26 percent two-year survival with standard care alone.

    Vaccines for brain tumors are new and experimental, said Lesser, but are gaining more attention in the glioma world. "Vaccines are a way to harness the body's own defenses -- which are usually used to ward off or control infections like the flu -- to fight cancer cells instead," Lesser explained. "It is a way of presenting antigens or proteins normally found on the surface of the cancer cells to the immune system so that immune cells can seek out and kill those cancer cells anywhere in the body. This is not unlike giving a piece of clothing to a bloodhound and then letting it loose to find a missing person."

    Wake Forest Baptist is also involved in another brain tumor vaccine trial for patients with low-grade or slower growing gliomas. Among the targets of both of these vaccines is a new protein found on the surface of glioma cells discovered by Waldemar Debinski, M.D., Ph.D, director of the Wake Forest Baptist Brain Tumor Center of Excellence.

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Finally ...

CHEMO ALONE TRUMPS CHEMO PLUS RADIATION FOR EARLY-STAGE HODGKIN LYMPHOMA

    In patients with limited-stage HODGKIN LYMPHOMA, treatment with ABVD CHEMOTHERAPY alone led to better overall survival than a strategy that includes subtotal nodal radiation therapy, according to new research presented at the 53rd annual meeting of the American Society of Hematology.

    Patients with limited-stage Hodgkin lymphoma (HL) are often treated with adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) plus radiation. But investigators from the National Cancer Institute of Canada (NCIC) Clinical Trials Group (CTG), together with the Eastern Cooperative Oncology Group (ECOG), believed that dropping radiotherapy might result in equally good outcomes without the long-term toxic effects of radiation.

    "We believed that ABVD chemotherapy alone would provide comparable disease control and be associated with fewer deaths due to late treatment effects from extended-field radiation therapy," said lead author Dr. Ralph M. Meyer, from Queen's University, Kingston, Ontario, Canada.

    In what they said was the final analysis of data from a phase III trial, the researchers compared the 12-year outcomes of approximately 400 patients with non-bulky clinical stage I-IIA HL who had been stratified into low and high-risk groups and then randomized to receive ABVD alone, or extended-field radiation therapy with or without ABVD.

    Overall survival, the primary endpoint, was 94% with chemotherapy alone and 87% with radiation.

    An analysis of the results in the high-risk patients revealed similar findings, with 92% of patients in the ABVD only arm achieving overall survival at 12 years, compared with 81% patients in the ABVD plus radiation arm.

    There were 12 deaths in the chemotherapy-alone arm, six due to Hodgkin lymphoma and six due to other causes. In the radiation group, there were 24 deaths, but only four were due to Hodgkin lymphoma. The other 20 were due to other causes, including 10 second cancers.

    "This study shows that ABVD alone is associated with a lower risk of second cancers and heart problems," Dr. Meyer said. "Until these results, minority opinion would be to give chemotherapy alone. I think what you'll see now is that swings to become a majority opinion."  He also noted that a major limitation of the study is that radiation protocol is now outdated; by today's standards it would be considered excessive. This means that some of the downside that was seen with the radiation may be exaggerated.

    "Nonetheless, our results are very comparable to the best results reported now using less chemo and modern radiation. Even with modern radiation there will be risks of giving radiation to the chest and the heart area. In women the radiation field will include part of the breast, so there is a risk of breast cancer, it will include part of the lung, so there is the risk of lung cancer, and of course the skin is always exposed and so there is the risk of melanoma," he said.

    He added: "Patients will need to be told there's a slight risk of the cancer coming back by not giving radiation, but in the long-term, getting chemotherapy alone has advantages of avoiding long-term effects of the radiation."

    The study was published in the New England Journal of Medicine to coincide with its presentation at the conference.

    Dr. Jane N. Winter, from Northwestern University Feinberg School of Medicine in Chicago, who was the ECOG chair of the trial, said she believes that the findings will encourage the "growing trend in the U.S. to use chemotherapy alone in early stage patients."

    Early positron emission technology (PET) scanning for patients receiving chemotherapy alone can be used to monitor for signs of recurrence, she added.  "There are ongoing trials incorporating early PET-scanning for early stage patients that do not include radiotherapy, and need the support of the community to provide additional evidence for this strategy."

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See you next month ...