Toxic mushroom-based drug may help battle colorectal cancer

For some time, cancer scientists have considered the toxin, alpha-amanatin derived from “death cap” mushrooms, as a possible cancer treatment. However, due to its penchant for causing liver toxicity, its potential as an effective therapy has been limited.

Researchers at The University of Texas MD Anderson Cancer Center looked at antibody drug conjugates (ADCs) based on alpha-amanatin as one solution. They found that ADCs, when aimed at a gene called POLR2A, are highly effective in mouse studies in treating colorectal cancer. The drug caused complete tumor regression and greatly reduced toxicity. ADCs allow for improved targeting of cancer cells, resulting in less impact on healthy cells.

Xiongbin Lu, Ph.D., associate professor of Cancer Biology, observed that when the common tumor suppressor gene, TP53 is deleted resulting in cancer growth, another nearby gene, POLR2A is also deleted. Normal cells have two copies of POLR2A and TP53 genes. Lu’s study targeted cancers that had a single copy of both genes, representing 53 percent of colorectal cancers, 62 percent of breast cancers and 75 percent of ovarian cancers.

POLR2A is an essential gene for cell survival, including cancer cells,” said Lu. “Because there is only one copy, the cancer cells are more susceptible to suppression of this gene.”

Lu’s study was published in the April 22, 2015 issue of Nature.

Discovering that POLR2A is deleted at the same time as TP53 means that therapies can more narrowly target the genetic processes allowing cancer cells to thrive. Understanding that one copy of POLR2A can allow cancer to grow gives researchers a new target to hit. As it turns out, it can be suppressed by an ADC based on the mushroom toxin. Lu’s team tested the drug, alpha-amanatin as it was believed that it specifically inhibited POLR2A.

A tremendous effort has been made to restore TP53 activity in cancer therapies,” said Lu. “However, no TP53-based therapy has been successfully translated into clinical cancer treatment due to the complexity of TP53 signaling. POLR2A encodes an enzyme that is inhibited by alpha-amanatin. We found that suppression of POLR2A with low-dose alpha-amanatin stopped cancer cell growth and reduced toxicity.”

We anticipate that inhibiting POLR2A will be a novel therapeutic approach for human cancers harboring such common genomic alterations,” said Lu

Liu et al. TP53 loss creates therapeutic vulnerability in colorectal cancer. Nature. 2015; doi:10.1038/nature14418 [Abstract]

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Cancer scan could remove the need for radiotherapy in some patients

A UK National Cancer Research Institute trial led from The University of Manchester and the Christie NHS Foundation Trust has suggested that in patients with early stage Hodgkin lymphoma the late effects of radiotherapy could be reduced by using a scan to determine those who actually need it.

In a paper published in the New England Journal of Medicine, the researchers show that a positron-emission tomography (PET) scan immediately after treatment with chemotherapy can identify patients who have a very good outcome without additional radiotherapy.

Hodgkin lymphoma is a cancer that develops in the lymphatic system, which is a network of vessels and glands spread throughout the body. Around 1,900 people a year, many of whom are teenagers and young adults, are diagnosed in the UK.

The current standard treatment is for all Hodgkin lymphoma patients to receive chemotherapy, followed by radiotherapy. However, this radiotherapy comes with undesirable late effects, such as cardiovascular disease and other cancers – despite the fact that they have already been cured of Hodgkin lymphoma.

The 602 patients who agreed to take part in the ‘RAPID’ trial had a PET scan performed after their chemotherapy. Patients who tested positive received radiotherapy. Those who tested negative were divided into two groups – one group of 211 patients received no further treatment, while the other group of 209 had the standard radiotherapy.

After three years of regular check-ups, the proportion of patients who were alive and free of disease was 94.6% in the radiotherapy group, and 90.8% in the group which hadn’t received further treatment.

Lead researcher, Professor John Radford, is based at The University of Manchester’s Institute of Cancer Sciences and the Christie NHS Foundation Trust. He said: “This research is an important step forward. The results of RAPID show that in early stage Hodgkin lymphoma radiotherapy after initial chemotherapy marginally reduces the recurrence rate, but this is bought at the expense of exposing to radiation all patients with negative PET findings, most of whom are already cured.”

Despite the findings from this study the researchers stress that a longer follow-up period is needed in order to determine whether this approach will ultimately lead to fewer late side-effects and improved overall survival.

The research was funded by Leukaemia & Lymphoma Research. Dr Matt Kaiser, Head of Research at the charity, said: “This ground breaking clinical trial shows that, by using scans to predict an individual’s risk of relapse, many patients can remain disease-free with just chemotherapy alone. Radiotherapy can cause a range of long-term problems like heart disease and hard-to-treat second cancers. As many Hodgkin lymphoma patients are relatively young, it is particularly important to avoid using intensive treatment when it is unnecessary.”

Radford et al. Results of a Trial of PET-Directed Therapy for Early-Stage Hodgkin’s Lymphoma. N Engl J Med. 2015; 372:1598-1607, DOI:10.1056/NEJMoa1408648 [Article]

Triple negative breast cancer in African-American women has distinct difference

What makes triple negative breast cancer more lethal in African American women than White women or women of European descent? A new study reveals specific genetic alterations that appears to impact their prognosis and ultimately survival rates. The study will be presented at the American Association for Cancer Research (AACR) Annual Meeting 2015 in Philadelphia.

Luciane R. Cavalli, PhD, assistant professor at Georgetown Lombardi Comprehensive Cancer Center explains this new work:

Triple negative breast cancer is an aggressive subtype of breast cancer where limited treatment is available. These tumors are the leading cause of breast cancer death in African-American women, which are usually diagnosed at an earlier age and in more advanced stages of the disease, when compared with White women. The main objective of our study was to identify molecular markers in these patients that may be associated with their observed disparity in incidence and mortality rates.

Using genome-wide screening methods, we identified a distinct pattern of DNA copy number (genome regions with gains and losses) and miRNA (small non-coding regions in the genome) expression levels associated significantly with the African American triple negative breast cancer patients, when compared with White TNBC patients. This association was observed irrespectively of their clinical and pathological characteristics, including age, tumor size, stage and grade and presence of axillary lymph node metastasis.”

These initial findings indicate specific genetic alterations, involved in critical cancer related pathways and networks, in the triple negative breast cancer of African American women that might present an impact for their prognosis and treatment, ultimately contributing to an increase in their overall survival rate.”

American Association for Cancer Research (AACR) Annual Meeting 2015 in Philadelphia.

Physical activity benefits lung cancer patients and survivors

Exercise and physical activity should be considered as therapeutic options for lung cancer as they have been shown to reduce symptoms, increase exercise tolerance, improve quality of life, and potentially reduce length of hospital stay and complications following surgery for lung cancer.

Lung cancer is the leading cause of cancer deaths in the United States with an estimated 160,000 deaths each year and worldwide there are 1.4 million deaths. In the last two decades lung cancer therapy has improved, but the overall 5-year survival rate is still quite low at 17%. Lung cancer patients experience many debilitating symptoms including difficulty breathing, cough, fatigue, anxiety, depression, insomnia, and pain. A third of long term survivors, those >5 years from diagnosis, experience reduced quality of life and report lower physical and health scores compared to healthy patients. Given the incidence of lung cancer and the associated costs An inexpensive and relatively easy cancer therapy to reduce symptoms and improve quality of life, like physical activity, could be beneficial, especially for therapy, but clinicians underutilize exercise as a therapy, in part due to the lack of evidence-based consensus as to how and when to implement increasing physical activity.

Dr. Gerard A. Silvestri, Dr. Brett Bade, and colleagues at Medical University of South Carolina have reviewed the safety, benefits, and application of increasing physical activity and exercise in lung cancer with the goal to summarize the effect on improved lung cancer outcomes. Their results are published in the Journal of Thoracic Oncology, the official journal of the International Association for the Study of Lung Cancer (IASLC).

The authors found that most lung cancer patients (regardless of stage) want physical activity advice directly from a physician at a cancer center before cancer treatment and exercise guidance may increase compliance with a dedicated program.

Physical activity reduces risk of cancer development in multiple cancer types including lung. Large trials showed exercise’s association with reduced all-cause mortality and that self-reported moderately vigorous physical activity led to lower risk of all-cause and cancer-specific mortality. Multiple trials have shown that increased activity reduces symptom burden and that exercise interventions may have beneficial effects on quality of life, physical function, social function, and fatigue.

Perioperative exercise in lung cancer patients appears to be safe with improvement in operability, operative risk, post-operative complications, as well as increase exercise capacity. Preoperative interventions may be more beneficial than post. Non-surgical advanced-stage lung cancer patients may benefit from increased physical activity by improving exercise tolerance and symptom burden, though the location, duration, and intensity to be recommended is not clear.

Chronically-ill cancer patients have different exercise limitations than their healthy counterparts and other concurrent diseases and high symptom burden add challenges in how best to study and implement physical activity programs in lung cancer patients. Low-intensity regimens such as daily walking or step-counting may provide a safe mechanism to increase physical activity while identifying an individual patient’s activity limits. Both supervised and self-directed programs have potential benefit, though how to choose one versus the other is not yet clear.

The same benefits of increased activity observed in lung cancer patients, especially improved symptoms and quality of life, appear to apply to lung cancer survivors as well.

The authors conclude “clinicians should (at minimum) consider physical activity early, counsel against inactivity, and encourage physical activity in all stages of lung cancer patients and lung cancer survivors. This review shows uniform recognition that exercise and physical activity are safe for those with lung cancer, patients are requesting increased activity counseling, and multiple studies and reviews show potential clinical benefit in quality of life, exercise tolerance, and post-operative complications. Further, we know that inactivity in cancer patients is associated with worse outcomes.” However, “there are still large gaps in the published literature to be addressed and these could be filled with large definitive prospective trials that evaluate the benefit of exercise in lung cancer patients”.

Bade et al. Increasing physical activity and exercise in lung cancer: Reviewing safety, benefits, and application. J Thorac Oncol. 2015. doi:10.1097/JTO.0000000000000536 [Abstract]

Future Science Group announces free access to peer-reviewed journals focused on cancer

Future Science Group today announced that it will provide free access to three of its peer-reviewed, cancer-focused journals for the remainder of 2015. The journals, Hepatic OncologyMelanoma Management, and the International Journal of Endocrine Oncology present the latest findings in their area of research and treatment, together with authoritative reviews, cutting-edge editorials and perspectives that highlight hot topics and controversy in the field.

Given the critical importance of emerging research to every practitioner treating patients with cancer, we are very pleased to provide individuals with better access to new sources of quality information,” said Phil Garner, Managing Director of Future Science Group. “While the journals are relatively new, each offers in depth coverage of an area of cancer that demands more attention and resources.”

Hepatic Oncology publishes original research studies and reviews addressing preventive, diagnostic and therapeutic approaches to all types of cancer of the liver, in both the adult and pediatric populations. The quarterly journal also highlights significant advances in basic and translational research, and places them in context for future therapy.

For more details please see: http://www.futuremedicine.com/loi/hep

Melanoma Management launched in August 2014 and focuses on the clinical aspects of melanoma, from prevention to diagnosis and from treatment of early-stage disease to late-stage melanoma and metastasis. Published quarterly, Melanoma Management delivers an accessible overview of current and future melanoma management options in a concise format that is ideal for the busy clinician. The journal welcomes the unsolicited submission of article proposals and original research manuscripts.

For more details please see: http://www.futuremedicine.com/loi/mmt

International Journal of Endocrine Oncology is a quarterly, peer-reviewed journal that helps the clinician to keep up to date with best practice in a fast-moving field that covers a broad range of diseases, both malignant and benign. It presents research findings in diagnosis and management of endocrine cancer, including tumors of hormone-secreting glands, such as the pituitary, thyroid, pancreatic and adrenal glands, along with neuroendocrine tumors. Independent drug evaluations assess newly approved medications and their role in clinical practice.

For more details please see: http://www.futuremedicine.com/loi/ije

All of the journals welcome the unsolicited submission of article proposals and original research manuscripts. Select content can be accessed from the whole of Future Science Group’s Oncology collection. Plus, via Oncology Central, Future Science Group’s free eCommunity for oncology professionals, users can access breaking news, articles and other essential current information, all aimed and selected by fellow trusted clinicians.

Avoid eating herring and mackerel during chemotherapy

Researchers found that consuming the fish herring and mackerel, as well as three kinds of fish oils, raised blood levels of the fatty acid 16:4(n-3), which experiments in mice suggest may induce resistance to chemotherapy used to treat cancer, according to a study published online by JAMA Oncology.

Patients with cancer often adopt lifestyle changes and those changes often include the use of supplements. But there is growing concern about the use of supplements while taking anticancer drugs and the possible effect on treatment outcomes, according to the study background.

Emile E. Voest, M.D., Ph.D., of the Netherlands Cancer Institute, Amsterdam, and coauthors examined exposure to the fatty acid 16:4(n-3) after eating fish or taking fish oil.

The authors examined the rate of fish oil use among patients undergoing cancer treatment, while researchers also recruited healthy volunteers to examine blood levels of the fatty acid after ingestion of fish oils and fish. The fish oil portion included 30 healthy volunteers and the fish portion included 20 healthy volunteers.

Among 118 cancer patients who responded to a survey about the use of nutritional supplements, 35 (30 percent) reported regular use and 13 (11 percent) used supplements containing omega-3 fatty acids, according to the results.

The study found increased blood levels of the fatty acid 16:4(n-3) in healthy volunteers after the recommended daily amount of 10 mL of fish oil was administered. An almost complete normalization of blood levels was seen eight hours after the 10-mL fish oil dose was given, while a more prolonged elevation resulted after a 50-mL dose, according to the results.

Eating 100 grams of herring and mackerel also increased blood levels of 16:4(n-3) compared with tuna, which did not affect blood levels, and salmon consumption, which resulted in a small, short-lived peak.

Taken together, our findings are in line with a growing awareness of the biological activity of various fatty acids and their receptors and raise concern about the simultaneous use of chemotherapy and fish oil. Based on our findings, and until further data become available, we advise patients to temporarily avoid fish oil from the day before chemotherapy until the day thereafter,” the study concludes.

Daenen et al. Increased plasma levels of chemoresistance-inducing fatty acid 16:4(n-3) after consumption of fish and fish Oil. JAMA Oncol. 2015. doi:10.1001/jamaoncol.2015.0388 [Article]