Merck’s Keytruda wins FDA approval to treat head and neck cancer

Source: Reuters
Date: June 11, 2019
Author: Reporting by Aakash Jagadeesh Babu; Editing by Shailesh Kuber

(Reuters) – Merck & Co Inc said on Tuesday its blockbuster cancer drug Keytruda won approval from the U.S. Food and Drug Administration to treat a type of head and neck cancer.

The drug was approved for use as a monotherapy, as well as in combination with a common chemotherapy regimen, to treat previously untreated patients with head and neck squamous cell carcinoma, Merck said.

The approval is based on results from a late-stage trial, where Keytruda showed a significant improvement in overall survival in cancer patients, Merck said.

Keytruda, a type of immunotherapy called a PD-1 inhibitor, is already an approved treatment for several forms of cancer, including lung and skin cancers.

Head and neck cancer includes tumors in the mouth, tongue, nose, sinuses, throat and lymph nodes in the neck.

Merck estimates that there will be more than 65,000 new cases of head and neck cancer diagnosed in 2019 in the United States.

Keytruda works by increasing the ability of patients’ immune system to help detect and fight tumor cells.

The drug has been amassing approvals as a standalone therapy and in combination with other drugs to treat several forms of cancer. It is the leading immunotherapy for treating lung cancer, ahead of rival drugs from Bristol-Myers Squibb, Roche and AstraZeneca.

Keytruda, first approved for advanced melanoma in 2014, is Merck’s most important growth driver. It has overtaken Bristol’s Opdivo as the industry’s immuno-oncology leader with sales expected to top $10 billion this year and $20 billion in 2024, according to IBES data from Refinitiv.

Keytruda brought in revenue of $7.17 billion for Merck in 2018, while Bristol’s Opdivo earned $6.74 billion.

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June, 2019|Oral Cancer News|

Merck’s Keytruda wins FDA approval to treat head and neck cancer

Source: www.pharmalive.com
Author: staff, Reuters Health

Merck & Co Inc said on Tuesday its blockbuster cancer drug Keytruda won approval from the U.S. Food and Drug Administration to treat a type of head and neck cancer.

The drug was approved for use as a monotherapy, as well as in combination with a common chemotherapy regimen, to treat previously untreated patients with head and neck squamous cell carcinoma, Merck said.

The approval is based on results from a late-stage trial, where Keytruda showed a significant improvement in overall survival in cancer patients, Merck said.

Keytruda, a type of immunotherapy called a PD-1 inhibitor, is already an approved treatment for several forms of cancer, including lung and skin cancers.

Head and neck cancer includes tumors in the mouth, tongue, nose, sinuses, throat and lymph nodes in the neck.

Merck estimates that there will be more than 65,000 new cases of head and neck cancer diagnosed in 2019 in the United States.

Keytruda works by increasing the ability of patients’ immune system to help detect and fight tumor cells.

The drug has been amassing approvals as a standalone therapy and in combination with other drugs to treat several forms of cancer. It is the leading immunotherapy for treating lung cancer, ahead of rival drugs from Bristol-Myers Squibb, Roche and AstraZeneca.

Keytruda, first approved for advanced melanoma in 2014, is Merck’s most important growth driver. It has overtaken Bristol’s Opdivo as the industry’s immuno-oncology leader with sales expected to top $10 billion this year and $20 billion in 2024, according to IBES data from Refinitiv.

Keytruda brought in revenue of $7.17 billion for Merck in 2018, while Bristol’s Opdivo earned $6.74 billion.

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Antibodies against HPV16 can develop up to 40 years before throat cancer is diagnosed

Source: www.eurekalert.org
Author: news release

An international group of researchers has found that antibodies to the human papilloma virus type 16 (HPV16) develop in the body between six to 40 years prior to a clinical diagnosis of throat cancer, and their presence indicates a strong increased risk of the disease.

The study, which is published in the leading cancer journal Annals of Oncology [1] today (Wednesday), also found that having HPV16 antibodies increased the risk of throat cancer far more in white people than in black: nearly 100-fold in white people, but 17-fold in black people.

Patients with HPV-associated throat cancer tend to respond better to treatment than those whose cancer is not associated with the infection; the researchers say this may partly explain the worse survival rates among black patients.

The main causes of throat cancer (known as oropharyngeal squamous cell carcinoma, OPSCC) are smoking, alcohol use and infection with HPV16. In the USA the proportion of OPSCCs attributable to HPV16 is around 70%; in some European countries a similar proportion is caused by HPV16, although this varies from country to country. [2]

Dr Mattias Johansson, a cancer epidemiologist at the International Agency for Research on Cancer (IARC) in Lyon, France, who led the research, said: “Importantly, the proportion of throat cancers caused by HPV16 has been increasing over the past few decades, particularly in men, and in some countries the overwhelming majority are now caused by the virus.

“Investigating the range in time prior to diagnosis in which HPV antibodies develop is important to understand how many years an individual who tested positive would be at increased risk, and also gives important insight into the natural history of the disease. In this study we found that antibodies can, in some cases, develop several decades prior to diagnosis of cancer. If rates of throat cancer continue to rise in the future, this biomarker could provide one means to identify individuals at very high risk of the disease who may benefit from specific preventive measures.”

The researchers from Europe, North America and Australia, who were part of the HPV Cancer Cohort Consortium, looked at 743 patients with throat cancer and compared them with 5,814 people without cancer who were the control group [3]. In the years before any diagnosis of cancer, all patients provided at least one blood sample, which was tested for antibodies against the HPV16 cancer-causing E6 protein, and 111 patients provided multiple samples over a period of up to 40 years. The median (average) time between first blood sample collection and a diagnosis of OPSCC was just over 11 years.

Specifically, they found that HPV antibodies were present in only 0.4% of people in the control group (22 out of 5814), but were detected in 26.2% of OPSCC patients (195 out of 743). Antibodies were present in 27.2% of white people before diagnosis with OPSCC (191 of 701) and in 7.7% of black people (3 of 39). This means that the presence of HPV16 antibodies was associated with a 98.2-fold increase in the risk of OPSCC in white people and a 17.2-fold increase in black people.

The first author of the study, Dr Aimée Kreimer, senior investigator at the Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, USA, said: “We also found that people diagnosed in more recent calendar years were more likely to have HPV antibodies, which is consistent with what we know about the increase in the proportion of throat cancers that are due to HPV16. Although there were some people with HPV antibodies detected prior to 1995, this was relatively rare.”

The researchers found that HPV16 antibodies tended to appear in people aged between about 40 to 80 years old – the median age at which antibodies were detected was 52 years, while the median age of diagnosis with OPSCC was 62. As there is no suitable, evidence-based way to test for OPSCC before symptoms appear, more research will be needed before HPV16 antibodies could be used to detect OPSCC in its early, pre-symptomatic stages.

Dr Kreimer said: “Although HPV16 antibodies could be a way to identify people at very high risk of cancer, we are currently missing the critical next steps in the screening process. Also, even though the antibody marker was very good at discriminating between those who would develop cancer and the controls who would not, with such a rare cancer, many people would still be likely to have a false-positive results.”

Dr Johansson concluded: “Future studies will focus on the most appropriate way to follow-up individuals who test positive for HPV16 antibodies and whether there is a way to identify pre-malignant lesions, as well as alternative ways of reducing the risk of eventually developing OPSCC. In other words, there is a long way to go before this biomarker can be used in clinical practice. While vaccination against HPV holds promise in preventing HPV-related cancers, we will not see a resulting reduction in throat cancers for several decades.”

Reasons why HPV16-driven throat cancer has increased in recent decades include changes in sexual practices that started in the middle of the 20th century and a decrease in tonsillectomy rates, which results in more tissue being available for infection by the virus.

The main limitation of the study is the difference between the groups of patients who took part in the study. For example, the group with the longest period of time between first collection of blood and diagnosis of OPSCC came from Norway, while other patient groups tended to have fewer blood samples collected over shorter timescales.

The research was carried out in collaboration with Dr Tim Waterboer, Head of Infection and Cancer Epidemiology, at the German Cancer Research Centre (DKFZ) in Heidelberg, Germany, who developed the HPV16 antibody test.

Notes:
[1] “Timing of HPV16-E6 antibody seroconversion before OPSCC: findings from the HPVC3 consortium”, by A.R. Kreimer et al. Annals of Oncology. doi:10.1093/annonc/mdz0138

[2] Oropharyngeal cancer starts inside the throat directly behind the nose, and can include the base of the tongue and tonsils. It is still a relatively rare cancer. Worldwide there are approximately 500,000 cases of head and neck cancers, of which OPSCC is one type. It is twice as common in men as in women.

[3] Of the 743 OSCC patients, 66% were from Europe, 30% from North America and 4% from Australia.

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Researchers zero in on new class of oral cancer drugs

Source: UT Health San Antonio
Date: June 3, 2019
Author: Rosanne Fohn

SAN ANTONIO (June 3, 2019) ― Researchers at UT Health San Antonio have identified a potent new class of anti-cancer drugs that target oral cancer cells while leaving other cells unharmed. The new drug class also has shown promise in stopping other types of cancer.

In two recent papers, a research team led by Cara Gonzales, D.D.S., Ph.D., developed a new class of drugs broadly referred to as capsazepine analogs and tested them against oral and other types of cancers in preclinical and animal studies.

Low survival rate for advanced and recurrent oral cancer

“Our main goal was to develop cancer-targeting drugs to effectively treat advanced and recurrent oral cancer,” said Dr. Gonzales, an associate professor in the School of Dentistry’sDepartment of Comprehensive Dentistry. “This is important because oral cancer is a deadly disease with a five-year survival rate of only 40 percent,” she said. “Oral cancer is rarely diagnosed in its earliest stages when it can be cured. About 75 percent of patients come to the clinic with advanced disease, dramatically lowering their chance of survival,” she said.

The team’s previous research showed that capsazepine is a potent cancer killer. Capsazepine is a synthetic cousin of capsaicin, the substance in chili peppers that gives them their heat. While studying oral cancer pain, Dr. Gonzales’ team discovered that capsazepine has significant cancer-fighting activity through a cancer-selective mechanism of action. In collaboration with the Center for Innovative Drug Discovery, a partnership of UT Health San Antonio and The University of Texas at San Antonio, more potent capsazepine analogs were developed with significantly stronger anti-cancer efficacy in mouse models of oral cancer and no adverse effects on healthy tissue.

Two papers show progress

In a paper published in Bioorganic & Medicinal Chemistry in November, Dr. Gonzales’ team describes their work synthesizing 30 new compounds whose chemical structures were based on the parent compound, capsazepine. The compounds were then screened based on their ability to kill oral cancer cells in culture. Lead compounds CIDD24, CIDD99 and CIDD111 were validated in mouse models of human cancer.

This data informed additional preclinical and animal work outlined in the second paper, published in March in the Journal of Oral Pathology & Medicine. These studies zeroed in on the most effective lead compound, CIDD99. This compound eradicated the tumors while leaving normal healthy tissue unaffected. An added benefit was that CIDD99 also sensitized oral cancer cells to traditional chemotherapies, meaning that much lower doses of chemotherapy could be used with dramatically greater effectiveness and fewer side effects.

Drugs effective against other types of cancer

CIDD99 was also effective against a panel of other cancer types and therefore may provide a new therapy for multiple cancers with fewer side effects than traditional chemotherapies. “As we got further into our research, we found that CIDD99 also is effective against non-small-cell lung cancer, triple-negative breast cancer and prostate cancer cells,” Dr. Gonzales said.

“These results are very exciting because no new drugs have been developed in over 40 years to treat oral cancer. While immunotherapy works very well, it is only effective in a small group of patients. Our compounds may provide a new class of drugs that may be effective for all oral cancer patients,” she added.

Patents filed on three drugs

UT Health San Antonio and UTSA have a patent on the three drugs through the Office of Technology Commercialization, which serves both universities as a catalyst for stimulating innovation and entrepreneurship among faculty, staff and students and industry partners through the UT System.

Researchers working toward human clinical trials

The research team is now working with venture capital companies to apply for Small Business Technology Transfer grants and an American Cancer Society Mission Boost Phase 1 grant to conduct additional preclinical studies that are required before applying to the U.S. Food and Drug Administration for an Investigational New Drug (IND) status. An IND designation authorizes the administration of an experimental agent in humans enabling future clinical trials.

“These grants will help us generate additional data regarding safety, toxicity and how they work in the body that will get us ready to submit our FDA application for human trials,” Dr. Gonzales said.

The research was supported by an Institute for Integration of Medicine and Science Clinical and Translational Science Pilot Award and a San Antonio Life Science Sciences InstituteCenter for Innovative Drug Discoveries Pilot Grant.

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For current news from the UT Health Science Center San Antonio, now called UT Health San Antonio™, please visit our online newsroom, like us on Facebook or follow us on Twitter.

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The University of Texas Health Science Center at San Antonio, now called UT Health San Antonio®, is one of the country’s leading health sciences universities. With missions of teaching, research, healing and community engagement, its schools of medicine, nursing, dentistry, health professions and graduate biomedical sciences have produced 36,500 alumni who are leading change, advancing their fields and renewing hope for patients and their families throughout South Texas and the world. To learn about the many ways “We make lives better®,” visit www.uthscsa.edu.

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June, 2019|Oral Cancer News|

Robotic surgery for oropharyngeal cancer not better than radiation therapy, study finds

Source: News Medical
Date: June 7, 2019
Author: Reviewed by James Ives, M.Psych (Editor)

In 2012, scientists at Lawson Health Research Institute launched the world’s first clinical trial comparing robotic surgery to radiation therapy for the treatment of oropharyngeal cancer (cancer at the back of the throat). The team is now reporting findings from the seven-year study which challenges beliefs that surgery leads to better swallowing outcomes, suggesting instead that radiation results in better quality of life for patients.

For Betty Ostrander, an operating room nurse from Tillsonburg, Ontario, a throat cancer diagnosis was life-changing. Betty was 59 when she discovered a small lump on the right side of her neck. After seeking medical care and testing, she was told she had oropharyngeal cancer.

“I remember thinking ‘I’m healthy, I eat right and I exercise; this can’t be happening to me.’ But it was, and it was scary,” recalls Betty. “One of the first questions I asked was whether there were any clinical trials available.”

Betty was one of 68 research participants in the ORATOR trial. The study included six centres from across Canada and Australia, including London Health Sciences Centre’s (LHSC) London Regional Cancer Program. Participants were randomized to receive either precision radiation therapy, often combined with chemotherapy, or transoral robotic surgery (TORS).

TORS is a surgical method for treating throat cancer which uses a small 3D camera and miniature robotic instruments to remove tumors. LHSC was the first center in Canada to offer TORS in 2011.

“Early studies suggested TORS might reduce the risk of swallowing problems historically associated with radiation and it therefore rose quickly in popularity,” explains Dr. Anthony Nichols, Associate Scientist at Lawson and Head and Neck Cancer Surgeon at LHSC. “But there was no randomized trial to compare patients’ swallowing outcomes. As the first center in Canada to offer TORS, we decided to tackle this problem through the ORATOR trial.”

The research team found no difference in survival between the two groups but, surprisingly, participants in the radiation group experienced better swallowing outcomes. A mild decline in swallowing function was observed in 40 per cent of the surgery participants compared to 26 per cent of radiation participants. All participants were able eat a full diet after treatment but 16 per cent from the surgery group said they needed to specially prepare their food.

Our findings challenge the notion that TORS leads to better swallowing outcomes. While radiation was previously associated with poor swallowing outcomes, treatments have advanced considerably and are now much more precise, which may be leading to better patient outcomes.”

Dr. David Palma, Associate Scientist at Lawson and Radiation Oncologist at LHSC

Patients in the surgery group were also at risk for dangerous bleeding during surgery. One year after treatment, patients in the surgery group were more likely to experience pain (22 per cent versus eight per cent in the radiation group), use painkillers (45 per cent versus 15 per cent), have issues with their teeth (12 per cent versus one per cent), and experience shoulder impairment.

The team found that patients in the radiation group experienced more short-term constipation and a temporary drop in blood counts. They also experienced an increased risk of tinnitus (ringing in the ears) and high frequency hearing loss when receiving chemotherapy, with some needing hearing aids.

“Each therapy has its different potential side effects but our findings suggest that TORS is not superior to modern radiation,” says Dr. Nichols. “We hope this research can be used by patients and their oncologists to help inform treatment decisions.”

Cases of oropharyngeal cancer have more than doubled since the 1990s. While throat cancer was more common in elderly patients with a history of heavy smoking or drinking, physicians have seen a dramatic rise in cases caused by human papilloma virus (HPV).

There is fortunately a high survival rate in patients with HPV-related throat cancer, leading researchers to study quality of life after treatment.

Drs. Nichols and Palma recently launched the ORATOR 2 trial which will further compare TORS against radiation and chemotherapy. The goal is to reduce the intensity of radiation and chemotherapy to improve quality of life while maintaining survival rates. The team aims to recruit 140 participants.

Results from the ORATOR trial were shared by Dr. Nichols at the American Society of Clinical Oncology’s Annual Meeting on May 31, 2019. The study was funded by the Canadian Cancer Society.

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June, 2019|Oral Cancer News|

Researchers training AI mobile app to detect early signs of oral cancer

Source: www.beckershospitalreview.com
Author: Andrea Park

Computer scientists have secured funding to develop artificial intelligence that can automatically identify signs of early-stage oral cancer using an existing screening app.

The project will build upon Cancer Research Malaysia’s Mobile Mouth Screening Anywhere (MeMoSA) app, which is currently used to capture images of the oral cavity for remote interpretation by oral medicine and surgical specialists. Researchers from the U.K.’s Kingston University and Malaysia’s University of Malaya will train a deep learning system to distinguish between thousands of photos with and without signs of oral cancer, then integrate that system into the app.

“Our challenge is to develop deep learning models that demonstrate a high accuracy and prediction of disease,” said lead researcher Sarah Barman, PhD, a professor of computer vision at Kingston. “If we find this approach is reliable enough, artificial intelligence could be used for other forms of disease screening with a wide range of possible applications in the field of medical diagnostics.”

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‘Game-changing’ new treatment for cancer patients available in Canada

Source: www.ctvnews.ca
Author: Jackie Vandinther, Digital Content Editor

In the last three years, David Hutson has beaten both throat and skin cancer. Now he’s hoping a new form of radiation treatment will help him overcome the prostate cancer he was diagnosed with last September. Hutson is the first patient in the world to experiment with a new cancer-killing technology called MR-Linac.

Radiologists from the Christie Hospital Manchester in the United Kingdom help cancer patient David Hutson out of the MR-Linac radiation machine in Manchester, U.K. in May 2019

Patient David Hutson receives radiation treatment for his prostate cancer using an MR-Linac machine at the Christie Hospital Manchester in Manchester, the United Kingdom in May 2019. (ITN)

“I feel very lucky indeed that I’m having this treatment. I feel very confident in this technology,” he says from the Christie Hospital Manchester in the United Kingdom.

“And from my diagnosis, it’s going to help me to defeat this third bout of cancer.”

Normally, radiotherapy is carried out in two stages. First, a scan of the tumour is made. Then a dose of radiation is delivered.

Part MRI scanner and part radiation machine, the MR-Linac allows doctors to do both tasks at once; they can visualize the tumour in real time while beaming high-energy radiation to the area. The result is on-the-spot imaging and targeted treatment in one shot.

Because doctors can give more precise and intense doses of radiation, the groundbreaking technology could treat cancers with unprecedented safety and efficiency. MR-Linac could also be an effective treatment for forms of cancer that move, or that are normally impossible to treat with radiation because of their proximity to vital organs, like the pancreas or liver.

Ananya Choudhury, a clinical oncology consultant at Christie Hospital Manchester, believes the new cancer-fighting technology has huge potential.

“If we can do that, then we can not only treat the patients with radiotherapy, but we can increase the dose to try and increase the cure rate,” he says.

Toronto’s Sunnybrook Hospital currently houses the only MR-Linac machine in Canada. Sunnybrook is also a founding member of an international consortium of doctors and experts leading the charge in developing this state-of-the-art device. Other members include medical centres in the United Kingdom, the United States and the Netherlands.

In March 2019, Health Canada approved a medical device license for the MR-Linac, a move that clears the machine to be sold commercially and used for research in Canada.

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A new way to predict complications after larynx cancer surgery

Source: www.eurekalert.org
Author: News release – Michigan Medicine, University of Michigan

Rebecca Hoesli, M.D., and Matthew Spector, M.D., evaluate an image from the studey

A technique that illuminates blood flow during surgery predicted which head and neck cancer patients were likely to have issues with wound healing. It could enable surgeons to make adjustments during surgery or recovery to improve outcomes.

A team of surgeons at the University of Michigan Rogel Cancer Center found the approach so successful in a clinical trial that they closed the study early.

Most people with larynx cancer will have radiation and chemotherapy. But about one-third of the time, the cancer will return or will prove resistant, leaving surgery as the next option.

At this point, tissue damage from the radiation adds challenges to the operation. When the surgeon closes the wound, damaged tissue can interfere. For about 40% of patients, this will lead to a pharyngocutaneous fistula, a hole in the neck where saliva can leak out. It can cause bleeding or infections, keeping patients in the hospital longer, and in 10% of cases sending them back to the operating room to fix it.

“Radiation damage is something you can’t always see. There have been very few examples in the literature that would explain or predict who’s going to have a complication,” says Matthew E. Spector, M.D., assistant professor of otolaryngology-head and neck surgery at Michigan Medicine. Spector is the senior author on a paper made available online in February ahead of final print publication in May in Annals of Surgical Oncology.

Researchers enrolled 41 patients who were undergoing laryngectomy after radiation. After removing the tumor but before closing the throat, anesthesiologists gave the patients an intravenous injection of a type of medical dye, indocyanine green. The dye circulates within about 40 seconds. Surgeons then use laser angiography, which illuminates the dye, allowing them to observe blood flow.

The results were clear-cut: patients with lower blood flow had a significantly higher risk of developing a fistula, whereas patients with high blood flow had a very low risk of wound complications.

Knowing this, Spector suggests a few possible interventions. One could be cutting out a wider margin of tissue to get a cleaner, healthier edge. Another possibility is to keep high-risk patients in the hospital longer, while sending the low-risk patients home more quickly.

The laser angiography approach would be straightforward to implement in many setting. It’s already used by other surgeons, including in breast reconstruction, so many hospitals already own the equipment. The technique has little impact on patients because it can be administered so quickly while they are still under anesthesia. Reactions to the indocyanine are minimal.

Researchers are developing a randomized clinical trial to assess whether cutting back more tissue leads to fewer fistulas in the high-risk group.

“We need to find an intervention that can lower this risk,” Spector says.

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Queensland scientist develops new HPV cancer vaccine

Source: 9News
Date: May 22, 2019
Author: 9News Staff

*click Source to view video*

Former Australian of the Year Professor Ian Frazer has developed a vaccine aimed at treating HPV-related cancers of the head, neck, throat and tongue.

While funding is still being finalised, a trial of the vaccine is being prepared for people with incurable oropharyngeal cancers.

Professor Frazer, the Scottish-born immunologist who developed and patented the vaccine against HPV-related cervical cancer, has been working on this vaccine for nearly 15 years.

While the cervical cancer vaccine works as a preventative, this new vaccine is a treatment therapy.

It works by teaching the patient’s immune system to target the cancer cells containing HPV. The patient will then be given immunotherapy drugs that supercharge the immune system.

“This is all about a new way to treat cancer using the body’s defence against infection,” Professor Frazer said.

“This might give a second chance at life.”

HPV-related throat cancer kills three Australians every day.

“It’s going to become a major problem in Australia, in fact in the US we’ve seen an increase in HPV-related throat cancers by 225 per cent,” head and neck radiation oncologist Sandro Porceddu said.

Professor Porceddu will conduct the trial at the Princess Alexandra Hospital. It should begin towards the end of this year if a further $700,000 in necessary funding is found.

© Nine Digital Pty Ltd 2019
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May, 2019|Oral Cancer News|

Greens and Genes

Source: Harvard Medical School
Date: May 16, 2019
Author: Jacqueline Mitchell

Your mother was right: Broccoli is good for you.

Long associated with decreased risk of cancer, broccoli and other cruciferous vegetables—the family of plants that also includes cauliflower, cabbage, collard greens, Brussels sprouts and kale—have now been found to contain a molecule that inactivates a gene known to play a role in a variety of common human cancers.

In a new paper published May 16 in Science, researchers led by Pier Paolo Pandolfi, the HMS Victor J. Aresty Professor of Medicine at Beth Israel Deaconess Medical Center, demonstrate that targeting the gene, known as WWP1, with the ingredient found in broccoli suppressed tumor growth in cancer-prone lab animals.

“We found a new important player that drives a pathway critical to the development of cancer, an enzyme that can be inhibited with a natural compound found in broccoli and other cruciferous vegetables,” said Pandolfi, who is also director of the Cancer Center and Cancer Research Institute at Beth Israel Deaconess.

“This pathway emerges not only as a regulator for tumor growth control, but also as an Achilles’ heel we can target with therapeutic options,” Pandolfi said.

One of the most frequently mutated, deleted, downregulated or silenced tumor suppressor genes in human cancersis PTEN. Certain inherited PTEN mutations can cause syndromes characterized by cancer susceptibility and developmental defects.

Because complete loss of the gene triggers an irreversible and potent failsafe mechanism that halts proliferation of cancer cells, it’s rare for both copies of the gene (humans have one copy from each parent) to be affected. Instead, tumor cells exhibit lower levels of PTEN. This raises the question of whether restoring PTEN activity to normal levels in the cancer setting can unleash the gene’s tumor-suppressive activity.

To find out, Pandolfi and colleagues identified the molecules and compounds regulating PTEN function and activation.

Carrying out a series of experiments in cancer-prone mice and human cells, the team revealed that a gene called WWP1, which is also known to play a role in the development of cancer, produces an enzyme that inhibits PTEN’s tumor-suppressive activity.

How to disable this PTEN kryptonite?

By analyzing the enzyme’s physical shape, the research team’s chemists recognized that a small molecule—formally named indole-3-carbinol (I3C), an ingredient in broccoli and its relatives—could be the key to quelling the cancer-causing effects of WWP1.

When Pandolfi and colleagues tested this idea by administering I3C to cancer-prone lab animals, they found that it inactivated WWP1, releasing the brakes on PTEN’s tumor-suppressive power.

But don’t head to the farmer’s market just yet. First author Yu-Ru Lee, HMS research fellow in medicine and a member of the Pandolfi lab, notes you’d have to eat nearly six pounds of Brussels sprouts a day, and uncooked ones at that, to reap their potential anti-cancer benefit.

That’s why the Pandolfi team is seeking other ways to leverage this new knowledge. The team plans to further study the function of WWP1 with the ultimate goal of developing more potent, and practical, WWP1 inhibitors.

Genetic or pharmacological inactivation of WWP1 with either CRISPR technology or I3C could “restore PTEN function and further unleash its tumor suppressive activity,” said Pandolfi. “These findings pave the way toward a long-sought tumor suppressor reactivation approach to cancer treatment.”

This work was mainly supported by the National Institutes of Health (grants R01CA82328 and R35CA197529).

In addition to Pandolfi and Lee, authors include Ming Chen, Jonathan D. Lee, Jinfang Zhang, Tomoki Ishikawa, Jesse M. Katon, Yang Zhang, Yulia V. Shulga, Assaf C. Bester, Jacqueline Fung, Emanuele Monteleone, Lixin Wan, John G. Clohessy, and Wenyi Wei, all of Beth Israel Deaconess; Shu-Yu Lin, Shang-Yin Chiang and Ruey-Hwa Chen of the Institute of Biological Chemistry; Tian-Min Fu and Chen Shen of Harvard Medical School; Chih-Hung Hsu, Hao Chen and Hao Wu of Boston Children’s Hospital; Antonella Papa of Monash University; Julie Teruya-Feldstein of Icahn School of Medicine at Mount Sinai; Suresh Jain of Intonation Research Laboratories; and Lydia Matesic of the University of South Carolina.

Disclosures: Pandolfi, Wei and Jain are cofounders of Rekindle Pharmaceuticals, which is developing novel therapies for cancer. All other authors declare no competing interests.

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May, 2019|Oral Cancer News|