human papillomavirus

Fighting throat cancer with T cells

Source: www.miragenews.com
Author: press release, Centenary Institute

Research led by the Centenary Institute has discovered that immune cells accumulating within the tumor environment, called tumor-resident T cells, are a critical determinant in survival rates of patients suffering from throat cancer.

Reported in the prestigious ‘Journal for ImmunoTherapy of Cancer’, the research suggests that strategies aiming to boost these T-cells at tumor sites could be beneficial to patients.

“Oropharyngeal squamous cell carcinoma (OPSCC) is a form of throat cancer. It can be caused by environmental factors such as smoking or by human papillomavirus infection (HPV), the same virus that causes cervical cancer in women,” said Ms Rehana Hewavisenti, lead author of the study and researcher at the Centenary Institute and the University of Sydney.

“We knew that patients with HPV-related OPSCC had far better clinical outcomes compared to other OPSCC patients but we didn’t know why,” she said.

In examining over sixty patient samples, Ms Hewavisenti and her colleagues discovered that increased levels of tumor-resident T cells, whether in HPV or non-HPV OPSCC cases, was clearly associated with improved patient survival outcomes.

“It was the accumulation of these immune T-cells, in and around the tumour site that appeared to be key,” said Ms Hewavisenti.

The researchers also found in their study that HPV OPSCC patients generally had far higher levels of tumour-resident T cells compared to their non-HPV OPSCC patient counterparts.

“We think these HPV positive patients tended to have better clinical outcomes as HPV infection is likely to favor the accumulation of these beneficial T-cells within the tumor area,” she said.

Dr Mainthan Palendira, Head of the Centenary Institute’s Human Viral and Cancer Immunology Laboratory and senior author on the research paper believes the research findings have major implications.

“Now that we understand how important this immune response is in relation to OPSCC, we can begin developing new treatment strategies focused on recruiting these favourable tumor-resident T cells directly to tumors,” he said.

Dr Palendira believes that looking at the amount of these T-cells in cancer could help clinicians to personalize the best treatment approach for individual patients.

“We also think that our research demonstrating viral (HPV) links with this tumor-resident T cell accumulation could help in future cancer vaccine development efforts too,” he said.

Experts release new guidelines for studies into most effective treatments for HPV-positive throat cancer

Source: en.brinkwire.com
Author: provided by University of Birmingham, United Kingdom

Heightened caution is needed when considering de-escalation trials for patients with Human papillomavirus (HPV)-positive oropharyngeal cancer (OPC), to ensure minimal harm to patients, new guidelines from a group of international head and neck cancer experts have suggested.

HPV-positive oropharyngeal cancer is a cancer of the throat caused by the human papillomavirus—a common, but symptomless group of sexually transmitted viruses. Instances of many throat and neck cancers have declined as smoking rates have fallen, whereas HPV-positive OPC has increased, largely affecting younger patients.

The standard course of treatment for this disease is a combination of cisplatin (a common chemotherapy drug) and radiotherapy. The younger age of the patient population, significantly improved prognosis, and relatively minimal morbidities caused by the standard treatment pathway have led to the popularisation of the concept of treatment de-escalation as a way to improve the quality of life of patients by reducing dosage or frequency of treatment.

These new recommendations, published today in the Journal of Clinical Oncology have been created by the Head and Neck Cancer International Group, a group of experts from nineteen countries, led by the University of Birmingham, UK. The guidelines have been prompted by the recent results of the first three randomised de-escalation trials which suggested a clear detriment in survival when cisplatin is omitted or substituted to minimise side effects.

After a review of available HPV-positive OPC literature, the guidelines recommend an overall need for caution when considering de-escalation options, even in instances where there appears to be possible favourable disease outcomes. Experts also recommend a revised approach to how findings are evaluated during phase II studies to ensure that any potential risks to survival are identified and only if none are present should phase III trials follow.

The guidelines also recommend that de-escalation trials should only be considered for well-defined, very low risk groups and only when there is a strong rationale for investigating a particular treatment strategy. Additionally harm-minimisation techniques should be considered as an alternative. Importantly, treatments should not be implemented into clinical practice before high level evidence is available.

Corresponding author Professor Hisham Mehanna, Director, Institute of Head and Neck Studies and Education (InHANSE) at the University of Birmingham said: “Clinicians and researchers have to be careful when planning and undertaking de-escalation studies, as trials to date have that harm can befall patient. Very controlled and small strides need to be taken when evaluating a possible de-escalation strategy, especially one that removes cisplatin.”

Less intense treatment safe for HPV+ throat cancer

Source: www.miragenews.com
Author: public release, University of Pittsburgh School of Medicine

A less intense treatment for human papillomavirus positive (HPV+) throat cancer—using robotic surgery followed by low-dose radiation—could provide as much benefit as standard higher-dose radiation and chemotherapy while preserving a patient’s throat function, and with potentially less toxicities, according to researchers at UPMC Hillman Cancer Center and Yale Cancer Center.

The results of their randomized phase two clinical trial will be presented virtually this week at the American Society of Clinical Oncology (ASCO) annual meeting during the Head and Neck Oral Abstract Session (Abstract 6500).

“These results present a promising deintensification approach that has proven to be safe in patients with intermediate risk, locally advanced oropharynx cancer,” said Robert Ferris, M.D., Ph.D., director, UPMC Hillman Cancer Center and a surgical oncologist specializing in head and neck cancer, who was lead investigator of the trial. The results are not yet published in a peer-reviewed journal.

About 60% of oropharynx cancer, in which cancer cells form in the back of the throat, base of the tongue and tonsils, is associated with HPV infection. The incidence has been increasing in recent years, especially in individuals under the age of 45.

Following robotic surgery, patients with HPV-associated throat cancer would typically undergo high dose radiation and chemotherapy. While robotic surgery allows for more precise and optimal preservation of the organs and surrounding tissue, there is still concern with the toxicities from the chemotherapy and consequences of tissue damage from radiation therapy, particularly in a younger population.

“Most throat cancers caused by HPV have good outcomes, and the cancer doesn’t return or spread to other parts of the body after treatment,” said Ferris, who also is professor, Department of Otolaryngology, of Immunology, and of Radiation Oncology, University of Pittsburgh School of Medicine.

“In this trial, we studied the pathologic features of the tumors obtained at surgery to determine patients’ risk of recurrence—low, intermediate or high—to then administer the right amount of postoperative treatment for each risk group.”

Patients at low risk were observed. Patients at intermediate risk were randomized to two arms of radiation alone, at standard or lower doses of radiation. Patients at high risk were assigned to usual high-dose radiation therapy plus chemotherapy.

For patients at low and intermediate risk, the two-year, progression-free survival rate was approximately 95%, and reducing radiation or chemotherapy intensity did not increase the risk of recurrence.

“The tissue samples and imaging studies collected in the course of this trial are a rich resource for studying the biology of intermediate- and high-risk disease, in work that is ongoing,” said ECOG-ACRIN Head and Neck Committee Chair Barbara Burtness, M.D., professor of medicine, and co-leader, Developmental Therapeutics Program, Yale Cancer Center and Yale School of Medicine.

Note:
The ECOG-ACRIN Cancer Research Group designed and conducted the trial with funding from the National Cancer Institute, part of the National Institutes of Health.

World-first saliva test detects hidden throat cancer

Source: www.miragenews.com
Author: staff

A simple saliva test developed by Queensland University of Technology (QUT) biomedical scientists has detected early throat cancer in a person who had no symptoms, and no clinical signs of cancer. QUT researchers Associate Professor Chamindie Punyadeera and Dr Kai Tang.

  • A series of saliva HPV tests detected an asymptomatic throat cancer during a trial of a new saliva diagnostic
  • Further validation studies are needed to confirm this finding
  • It is a world-first discovery, previously there was no screening test for HPV-DNA oropharyngeal cancers
  • The patient had surgery in which a 2mm cancer was removed and has had no recurrence of HPV-DNA in his saliva.

In what is believed to be a world-first, the non-invasive test picked up HPV-DNA in a saliva sample from an infected healthy person. Persistent human papillomavirus (HPV) infection is now the leading cause of cancers in the oropharynx (tonsils and tongue base area of the throat).

“The series of saliva tests raised the alert and detected an early cancer before the person had any symptoms,” said QUT Faculty of Health’s Associate Professor Chamindie Punyadeera, who, with Dr Kai Tang developed the test.

“This enabled removal of the tonsil which had a 2mm cancer in it, by straightforward local surgery alone.

“The incidence of high-risk human papillomavirus (HPV)-driven throat cancers is on the rise in developed countries and, unfortunately, it is often discovered only when it more advanced, with patients needing complicated and highly impactful treatment.

“In the US, HPV-driven throat cancers have surpassed cervical cancers as the most common cancer caused by HPV but unlike cervical cancer, up until now, there has been no screening test for this type of oropharyngeal cancer.”

Professor Punyadeera said the discovery was made during an HPV-prevalence study which included 665 healthy individuals.

“To take the test all the person has to do is give a salivary oral rinse sample. When the test shows HPV-16 DNA, it is repeated and if the presence of HPV-16 is persistent over a period of time we would be suspicious that there may be underlying cancer.

“The person whom we reported in this study had been consistently HPV-16 DNA positive for 36 months, with a steadily rising count of HPV-16 DNA after testing at 6, 12 and 36 months.

“The patient was found to have a 2mm squamous cell carcinoma in the left tonsil, treated by tonsillectomy. This has given our patient a high chance of cure with very straightforward treatment.

“Since the surgery, the patient has had no evidence of HPV-16 DNA in his saliva.”

Professor Punyadeera said this was the first-ever case of histologically confirmed diagnosis of an asymptomatic, hidden throat cancer, diagnosed with a saliva screening test and that wider validation studies were required to confirm this finding.

“The presence of this pattern of elevated salivary HPV-DNA must be fully evaluated, as it may provide the critical marker for early cancer detection.

“We now have the promise of a screening test for oropharynx cancer and there is an urgent need to undertake a major study to validate this test and the appropriate assessment pathway for people with persisting salivary HPV-DNA.

This research is part of a collaboration with Royal Brisbane and Women’s Hospital’s Professor Liz Kenny, Dr Sarj Vasani, Dr Touraj Taheri and Associate Professor Brett Hughes and University of Queensland’s Professor Laurence J. Walsh.

Source:
The study, An Occult HPV-Driven Oropharyngeal Squamous Cell Carcinoma Discovered Through a Saliva Test (https://www.frontiersin.org/articles/10.3389/fonc.2020.00408/full), was published in Frontiers in Oncology.

Novel intervention looks to improve timeliness, equity of head and neck cancer care delivery

Source: www.miragenews.com
Author: staff report, Medical University of South Carolina

Many factors go into surviving cancer.

Hollings Cancer Center researcher Evan Graboyes, M.D., specializes in head and neck cancer, a disease with poor survival prospects despite intense therapy with combinations of surgery, radiation and chemotherapy. While head and neck cancer only accounts for 4% of all cancer cases each year in the US, it has a high mortality rate. The American Cancer Society estimates that more than 14,000 patients died from this disease in the U.S. in 2019.

Overall, only 50% of head and neck cancer patients are alive at five years. Unfortunately, the mortality rate is even worse for African American head and neck cancer patients. That’s why researchers are looking for new strategies to improve patient survival and decrease racial disparities in outcomes for these patients.

Graboyes and MUSC Hollings Cancer Center researchers Chanita Hughes-Halbert, Ph.D., Katherine Sterba, Ph.D., Hong Li, Ph.D., and Graham Warren, M.D., Ph.D., have teamed up to develop and test a novel intervention to improve the timeliness, equity and quality of head and neck cancer care delivery, which they think might one day be the key to improving survival for these patients.

Funded by a $1.3 million 5-year grant from the National Cancer Institute, their study – Improving the Timeliness and Equity of Adjuvant Therapy Following Surgery for Head and Neck Cancer-started in September 2019 and built upon important research funded by grants from Hollings Cancer Center.

Graboyes explained that for patients with advanced head and neck cancer who are treated with surgery, national guidelines recommend that postoperative radiation therapy should start within six weeks of surgery.

“However, we know from our research that despite national guidelines, over half of the patients nationally don’t get radiation started in a timely fashion. Patients who have delays with radiation are more likely to die and have their cancer recur,” he said. “We are trying to find new ways to deliver timely head and neck cancer care. It’s an appealing way to help improve survival for this group.”

Innovative approach
The study is designed in three parts. The first part aims to identify the underlying reasons for why delays starting postoperative radiation are so common for this patient population. The researchers then developed a new multilevel health care delivery intervention called NDURE (Navigation for Disparities and Untimely Radiation thErapy), that specifically targets the barriers that lead to delays.

In the second part of the grant, the researchers will pilot the NDURE intervention in a small group of patients to make sure that it’s feasible and acceptable and refine the intervention based on participant feedback. In the third and final part of the study, they will compare NDURE to standard care in a randomized controlled trial to see whether NDURE is effective at decreasing treatment delays.

“This study interests me because it is clinically important. To help patients with head and neck cancer live longer, you don’t need to invent a new drug. All you need to do is get them the treatment they’re supposed to be getting. If we can find a way to deliver timely guideline-recommended care, it could have such a large impact on their survival,” he said

“It’s also a scientifically important study. Head and neck cancer treated with surgery followed by radiation is a great model system for us to understand how we deliver cancer care. Right now, we spend a lot of time and effort helping get people in to initiate cancer care. However, we understand a lot less about how cancer patients move through complicated treatment plans.”

Graboyes said South Carolina is primarily a rural state with some geographic barriers that present obstacles for patients to navigate. “Many of the patients will have surgery at a regional center like MUSC, then because radiation is five days a week for six weeks, they’ll get radiation at a different facility closer to where they live. We have to coordinate cancer care across health care systems, which presents some barriers that can lead to treatment delays.”

Graboyes emphasized that head and neck cancer is a major concern for the state of South Carolina and Hollings Cancer Center, a National Cancer Institute-Designated Cancer Center. The two major causes of head and neck cancer are smoking and human papillomavirus (HPV). The state’s population is affected by both, due to high rates of tobacco use and very low rates of HPV vaccination.

“As a result, Hollings has recognized this issue and has really invested a lot in the clinical enterprise of head and neck cancer because it’s such a problem in South Carolina.”

Hollings also has a strong cancer control program dedicated to reducing issues of health disparities and equity in the state, he explained.

“We think that NDURE, our intervention targeting the multilevel barriers to timely head and neck postoperative radiation, will be an effective way to help improve timely cancer care delivery for these patients, which will lead to higher rates of survival and low recurrence and decrease racial disparities and outcomes. That’s very exciting to our team.”

Did you know?
About 70% of cancers in the oropharynx (which includes the tonsils, soft palate and base of the tongue) are linked to HPV.

Dedicated to the mission of raising HPV vaccination rates for teens and young adults, Hollings Cancer Center has initiated a $700,000 three-year project. The Centers for Disease Control and Prevention recommends speaking with a doctor about the HPV vaccination. The HPV vaccine can prevent new infections with the types of HPV that most often cause oropharyngeal and other cancers.

April, 2020|Oral Cancer News|

The YAP signal plays a crucial role in head-and-neck cancer onset

Source: www.eurekalert.org
Author: press release, Kobe University

Joint research between Kobe University and National Hospital Organization Kyushu Cancer Center has revealed that mice with mutations in the YAP signal pathway develop head-and-neck cancer over an extremely short period of time (world’s fastest cancer onset mouse model), indicating that this pathway plays a crucial role in the onset of these cancers. This discovery may shed light on the development of new drugs for head-and-neck cancer.

This research resulted from a collaboration between a research group led by Professor SUZUKI Akira and Associate Professor MAEHAMA Tomohiko at Kobe University Graduate School of Medicine, and Dr. MASUDA Muneyuki’s team at Kyushu Cancer Center.

These results were published in the American scientific journal ‘Science Advances‘ on March 18.

Main Points:
>Deletion of MOB1 (*1, which represses YAP) in mouse tongues causes strong activation of YAP (*2), leading to the early onset of cancer (in about 1 week).

>In humans, the expression of YAP increases during the development of dysplasia (pre-cancerous lesions), prior to the onset of head-and-neck cancer. YAP continues to increase with the development and progression of cancer. This high YAP activation is linked to poor patient prognosis.

>The onset and progression of head-and-neck cancer in the mice in this study, and the proliferation of stem cells in this cancer in humans, are dependent on YAP.

>These results suggest that cancer develops when the YAP activation exceeds a threshold. YAP may play a fundamental role in head-and-neck cancer onset and progression. These conclusions represent a paradigm shift in the understanding of these cancers.

>The mouse model developed in this study can be used in research to develop new drugs for head-and-neck cancer and, in addition, provides a beneficial resource for cancer research in general.

>By inhibiting YAP, the development and progression of head-and-neck cancer can be suppressed. Thus, the YAP pathway provides a good target for head-and-neck cancer treatments.

Research Background

Head-and-neck cancer in humans
Head-and-neck cancer is the sixth most common type of cancer in the world, affecting 600,000 people annually. In Japan there are around 22,500 new cases every year. This ‘head and neck’ includes the oral cavity and areas of the throat (pharynx and larynx). Among these, mouth cancers (especially tongue cancer) are the most prevalent.

It is understood that exposure to carcinogens, such as those found in cigarettes and alcohol, as well as mechanical irritation of the mucous membranes in the mouth, tooth decay and improperly fitted dentures, are risk factors for the development of head-and-neck cancer.

In addition, 15% of head-and-neck cancer is caused by Human Papillomavirus (HPV), which in particular causes oropharynx cancer.

The prognosis for patients who are HPV-positive is relatively good. Conversely, prognosis is poor for HPV negative patients and in most cases, mutations are found in the tumor suppressor gene TP53 (p53). However, mutations in this gene alone are not sufficient to cause head-and-neck cancer. It has been thought that changes in other molecules are also necessary for cancer development, however these causes remain elusive.

From comprehensive cancer genome analyses, it is known that PTEN/P13K (46%), FAT1 (32%), EGFR (15%) gene mutations are also found in HPV-negative head-and-neck cancer. However, the genetic pathway of these molecules in relation to head-and-neck cancer development has not been sufficiently understood.

Mouse models of cancer
Up until now, research using mouse models of head-and-neck cancer has discovered that if both the p53 and Akt genes are mutated, 50% of mice will develop this type of cancer about 9 months after the mutation (the average mouse lifespan is 2 years).

The onset of cancer begins after many genetic mutations have accumulated (multistep carcinogenesis). Mice with a mutation in one important molecule usually develop cancer within 4 to 24 months (with the majority showing signs between 6 to 12 months).

The YAP pathway
The function of the transcriptional co-activator YAP is to turn ‘on’ the transcription of gene clusters related to cell growth. The LATS/MOB1 complex phosphorylates YAP, thereby excluding YAP from the nucleus, leading to the subsequent degradation of YAP proteins. In other words, MOB1 and LATS act as a ‘brake’ (tumor suppressor) to inhibit cell proliferation facilitated by YAP. It has been reported that in 8% of human head-and-neck cancer cases, the YAP gene is amplified and there is a connection between YAP activation, cancer progression and poor prognosis.

This research group produced mice with MOB1 deletion in their tongues (so that YAP would be intrinsically activated) in order to perform a detailed analysis in vivo of the role that the YAP pathway plays in head-and-neck cancer.

Research Methodology

Mice with MOB1 deletion exhibit rapid onset tongue cancer
This research group developed mice with MOB1 deletion in their tongues by applying the drug tamoxifen to their tongues and then modifying them genetically using the Cre-loxP system (*4).

Three days after applying tamoxifen, the amount of MOB1 had barely decreased, however by day 7, the vast majority of these proteins had disappeared. At this point, a third of the mice demonstrated rapid onset head-and-neck cancer (intraepithelial tongue cancer), with all mice developing the disease by day 14. The cancer had progressed in all mice by day 28 (invasive tongue cancer). The team succeeded in developing the world’s fastest mouse model of cancer onset. Both domestic and international patents for this model have been applied for.

This mouse model showed that head-and-neck cancer develops quickly (within a week) when the YAP pathway is strongly activated, suggesting that this pathway plays an extremely important role in head-and-neck cancer onset.

YAP activation and tumorigenic properties of the tongue epithelium in MOB1 deletion mice.
The epithelial cells (on the surface of the tongues) of MOB1 deletion mice exhibited the following properties characteristic of tumor development: increased cell proliferation and cell saturation density, impaired cell polarity, low levels of apoptosis (cell death), increase in undifferentiated cells, and chromosomal instability (characterized by increases in aneuploid cells (*5)), multipolar spindles (*6) and micronucleated cells). On a biochemical level, activation of YAP and a decrease in LATS proteins was evident due to MOB1 deletion.

The epithelial cells acquired the characteristics of tumor cells due to the YAP activation caused by the deletion of MOB1.

YAP activation in the stages of tongue cancer in humans
The development of human tongue cancer can be divided to the following stages; the normal stage, the dysplasia stage, the intraepithelial cancer stage (*8) and the invasive cancer stage (*9).

If we look at YAP activation across all these stages, we can see that YAP is enhanced in the dysplasia stage which proceeds the onset of cancer. YAP activation shows continued increase during the subsequent stages of cancer progression. In cases where YAP is highly activated, overall survival is decreased and the likelihood of cancer relapse is high.

In other words, YAP increases before the onset of cancer and continues to increase as the cancer develops and progresses. Accumulation of YAP is linked to poor patient prognosis.

Cancer formation is dependent on YAP when MOB1 is deleted
Invasive cancer occurred in MOB1 deletion mice. However, when both YAP and MOB1 are deleted from mice, cancer onset is halted at the dysplasia stage, showing that the onset of head-and-neck cancer is dependent on YAP (Figure 2).

Among current YAP pathway inhibitors, the SRC inhibitor Dasatinib (*10) was shown to be the most effective (SRC has been previously shown to activate YAP both directly and indirectly). Dasatinib was shown to prevent the onset of intraepithelial head-and-neck cancer in the MOB1 deletion mice. It also suppressed the development of invasive cancer in MOB1 deletion mice that had reached the intraepithelial head-and-neck cancer stage.

In human head-and-neck cancer stem cells, it is possible to suppress cell proliferation either by inhibiting YAP gene expression or by adding YAP inhibitors. Cisplatin, which is commonly used to treat head-and-neck cancer, is augmented when YAP is suppressed.

In mice, head-and-neck cancer onset and progression was suppressed when YAP was inhibited. In the same way, it was shown that in human tongue cancer stem cells, cell proliferation was also suppressed when YAP was inhibited.

Known genetic mutations in human head-and-neck cancer and YAP activation
Genetic mutations in p53, PTEN/PI3K, FAT1, and EGFR have been identified in HPV-negative head-and-neck cancer.

This research group showed that EGF signal activation and mutations in p53, PTEN and FAT1 each play a role in YAP activation. Furthermore, YAP activation gradually increases as these genetic mutations accumulate.

Normally, cancer takes time to develop as it is a multistep process. However, in this study, intraepithelial head-and-neck cancer rapidly developed just from highly strengthening YAP activation.

In conclusion, this study raises the possibility that the following process for head-and-neck cancer development takes place: A. Cancer develops when the YAP activation exceeds a threshold due to the accumulation of genetic mutations in p53, PTEN/PI3K, FAT1 and EGFR (Figure 3). B. Subsequently, YAP continues to accumulate after cancer has developed, resulting in cancer progression.

Conclusion and Further Developments
YAP is frequently activated in cancer cells although genetic mutations in the YAP pathway are not frequently found. It is thought that this is why the importance of the YAP pathway in the onset of head-and-neck cancer was unclear until now.

1. YAP activation levels are high before the onset of head-and-neck cancer in humans.
2. YAP is further activated as the cancer progresses.
3. The high frequency of mutations in p53, PTEN/PI3K, FAT1 and EGFR all activate YAP.
4. The accumulation of these molecular mutations gradually leads to high YAP activation:
4a. The accumulation of genetic mutations in p53, PTEN/PI3K, FAT1 and EGFR cause YAP to reach its threshold, culminating the onset of cancer.
4b. YAP continues to accumulate after the cancer onset, resulting in further cancer progression.

It is necessary to consider YAP as a basis for head-and-neck cancer onset and progression. This represents a paradigm shift in our understanding of these cancers.

In addition, it has also been shown that risk factors for head-and-neck cancer, such as cigarette smoking, mechanical irritation of mucous membranes and HPV infection, also play a part in YAP activation.

The mouse model in this study: 1. Is the fastest mouse model in the world for showing the natural onset of cancer. 2. Can be used to visualize cancer onset and progression. 3. Allows cancers to be developed naturally at the same time. 4. Allows cancer onset and progression to be analyzed in mice immediately after birth, allowing drug tests to be conducted in a shorter period of time and in small quantities. The results suggest that this mouse model would be ideal, not only for research into developing new treatments for head-and-neck cancer, but also for cancer research in general.

It is expected that the YAP pathway will provide a good target for drugs used in the treatment of head-and-neck cancer because inhibiting YAP not only suppresses the cancer onset but can also prevent its progression.

Researchers from all over the world, including this research group, are currently trying to find new drugs that target the YAP pathway. We have shown one factor that is effective against head-and-neck cancer. It is also expected that the mouse model will become an indispensable tool for evaluating their results and for head-and-neck cancer research.

Glossary
1. MOB1 (Mps One Binder 1): MOB1 is necessary for activating the LATS kinase and acts as a brake (tumor suppressor) on downstream, negatively-controlled YAP. Deletion of MOB1 exacerbates cell proliferation and leads to cancer.
2. YAP (Yes-associated Protein): YAP is a transcriptional coactivator. It forms a complex with multiple transcription factors inside the nucleus to control the expression of various genes. YAP is phosphorylated by the LATS kinase, causing YAP to be excluded from the nucleus and inactivated.
3. Human Papillomavirus (HPV): A type of papillomavirus, there are over a hundred genotypes or varieties of HPV. The virus is linked to genital warts, head-and-neck cancer and cervical cancer.
4. Cre-loxP system: A genetic modification system using Cre recombinase, which catalyze DNA recombination between two loxP sites (a 34-base pair nucleotide sequence). If Cre is expressed in a cell where chromosomal DNA has been artificially inserted into two loxP sites, the intervening DNA segment is deleted.
5. Aneuploid Cells: contain an abnormal number of individual chromosomes. This does not include a difference of one or more complete sets of chromosomes.
6. Multipolar Spindle: Spindles are formed during cell division to separate chromosomes between daughter cells. In normal cells, a pair of centrosomes forms prior to cell division to organize proteins called microtubules into a spindle between the two centrosomes. However, in cancer cells there are more than two centrosomes, and so-called multipolar spindles form. This can cause chromosomal instability and lead to the formation of aneuploid cells because the chromosomes were not correctly allocated at the time of cell division.
7. Dysplasia: The presence of cells of an abnormal type within a tissue. In medical diagnosis, the presence of abnormal-looking cells (dysplasia) observed under a microscope can signify an increased chance of a patient developing cancer (pre-cancerous symptoms).
8. Intraepithelial cancer: This is where cancer cells are found within the intraepithelial layer of cells which form on an organ’s surface. At this point, cancer cells have not been able to penetrate the basement membrane and have not spread deeply. Related terms include Carcinoma in Situ (CIS), intraepithelial tumor and intraepithelial neoplasia.
9. Invasive cancer: is where cancer cells penetrate the basement membrane, a thin membrane separating them from other tissues. From there, cancer can spread to the surrounding area.
10. Dasatinib: a chemotherapy drug that inhibits the SRC kinase family, which can cause malignant transformation in cells. SRC is both directly and indirectly connected to YAP activation, so dasatinib can also inhibit YAP. It is currently used to treat leukemia but is not prescribed for head-and-neck cancer treatment.

Acknowledgements:
This research was made possible primarily through funding to the project ‘The development of cancer treatment methods targeting cancer suppression genes.’ (Lead researcher: Suzuki Akira) as part of the Japanese Agency for Medical Research and Development’s Project for Cancer Research and Therapeutic Evolution (AMED P-CREATE).

March, 2020|Oral Cancer News|

Surveillance of ctDNA in HPV-positive head and neck cancers may predict recurrence

Source: www.targetedonc.com
Author: Nichole Tucker

The detection of circulating tumor DNA (ctDNA) in human papillomavirus (HPV) with an experimental blood test has been associated with high positive predictive value (PPV) and negative predictive value (NPV) for identifying disease recurrence in HPV-positive oropharyngeal cancer, according to a press release from the University of North Carolina (UNC) Lineberger Comprehensive Cancer Center.1

“The major utility of this test is it’s going to improve our ability to monitor patients after they complete treatment,” said Bhisham Chera, MD, associate professor in the UNC School of Medicine Department of Radiation Oncology. “Currently, our methods to assess whether the cancer has recurred are invasive, expensive and not always accurate.”

In a prospective biomarker clinical trial published in the Journal of Clinical Oncology, investigators obtained 1006 blood samples for their analysis, 999 of which were evaluable for plasma circulating tumor human papillomavirus DNA (ctHPVDNA). The goal was to determine if surveillance of ctHPVDNA can facilitate earlier detection of recurrence compared with normal clinical follow-up.2

Patients were followed for a median of 23.7 months (range, 6.1-54.7 months), and out of 115 patients, 13% developed disease recurrence (n = 15). Of these recurrences, 1 was local only, 1 was regional only, 10 were distant only, 1 was local and distant, and the remaining 2 were regional and distant. Following treatment, 87 patients had undetectable ctHPVDNA, and none developed recurrence (95% CI, 96%-100%). The development of a positive ctHPVDNA occurred in 28 patients during post-treatment surveillance.

The median time to abnormal ctHPVDNA signal was 12.3 months after complete chemoradiotherapy (CRT; range, 2.6-29.1 months). Sixteen patients had 2 consecutive positive ctHPVDNA results, and 15 of those patients developed biopsy-proven recurrence. The 2 ctHPVDNA blood tests that were consecutively positive had a PPV of 54% (95% CI, 0.339-0.725). A 3.9-month median lead time between ctHPVDNA positivity and biopsy-proven recurrence was observed (range, 0.37-12.9). the actuarial 2-year response-free survival (RFS) rate was 30% in patients who had an abnormal blood test during post-treatment surveillance compared with 100% among the remaining participants (P <.001).

In the study, CRT included cetuximab 250 mg/m2, carboplatin AUC 1.5, and paclitaxel 45 mg/m2. Patients received intravenous chemotherapy during intensity-modulated radiotherapy treatment, which was given weekly. There were 6 doses of chemotherapy in total.

The secondary end points of the study were local control rate, regional control rate, local-regional control rate, distant metastasis-free survival, OS, head and neck quality of life assessments, and speech and swallowing function.

Patients aged 18 years and older were eligible to enroll if they had T0-3, N0 to N2c, M0 squamous head and neck cancer, HPV and p16 positivity, radiologically confirmed hematogenous metastasis within 12 weeks before treatment, and ECOG performance status of 0 to 1, and adequate bone marrow, renal, and hepatic function. Individuals with prior history of radiation to the head and neck, head and neck cancer, those with unresectable disease, severe comorbidity, or known human immunodeficiency virus, or those taking disease-modifying rheumatoid drugs were excluded from the study.

Based on this research the investigators reported a 99% accuracy in confirming whether or not patients remained recurrence-free with their screening method, compared with other methods. For patients who had 2 HPV-positive blood tests, the accuracy was said to be 94%.1

“With this new technology, it offers a noninvasive way to accurately monitor patients for cancer recurrence,” Chera said. “In the long run, blood-based surveillance could be more effective, and possibly help us to detect cancer sooner.”

References
1. Study finds blood test accurately tracks HPV-linked head and neck cancer [news release]. Chapel Hill, North Carolina: University of North Carolina Lineberger Comprehensive Cancer Center; February 4, 2020. https://bit.ly/2tzlw7x. Accessed February 6, 2020.
2. Chera BS, Kumar S, Shen C, et al. Plasma circulating tumor HPV DNA for the surveillance of cancer recurrence in HPV-associated oropharyngeal cancer. J Clin Oncol. doi: 10.1200/JCO.19.01598.

February, 2020|Oral Cancer News|

What parents need to know about the HPV vaccine

Source: www.news-medical.net
Author: University of Chicago Medical Center, reviewed by Kate Anderton, B.Sc. (Editor)

The vaccine that prevents infection from human papillomavirus (HPV) is nothing short of a medical marvel. “It’s one of the most effective vaccines we have against any disease or infection. And it prevents cancer,” said Andrea Loberg, MD, clinical associate of obstetrics and gynecology.

Pre-teens and teens who are vaccinated against HPV can be spared some of the deadliest, most disfiguring and hard-to-treat cancers-;those of the cervix, vagina, vulva, penis, anus, mouth and throat. Over 90% of cancers caused by HPV can be prevented-;29,000 cases of cancer per year-;with the HPV vaccine.

Concerns about sexual promiscuity
To some parents, however, the HPV vaccine may be an uncomfortable reminder that their child will be moving into adulthood and may choose to express his or her sexuality. HPV is transmitted by oral, vaginal and anal sex and other intimate skin-to-skin contact, and it is extremely prevalent; about 80% of people will be exposed to the virus in their lifetime.

Condoms reduce but don’t eliminate the risk of HPV infections because the virus lives in both oral and genital tissues. Condoms do not cover the entire genital area of either gender. Nor are same-sex female partners protected from contracting the virus, which often causes no symptoms until precancerous lesions or cancer show up years later. “It’s hard for parents to think about our kids becoming sexually active, but we also want them to have fulfilling lives,” said Truehart, whose own two teenagers have received the HPV vaccine. “We want to make sure they are protected before they start having sex.”

The recommended age for receiving the HPV vaccine is 11 or 12, when children are also scheduled to receive the Tdap vaccine (tetanus, diphtheria and pertussis) and the meningitis vaccine. But the two-dose vaccine-;the second dose is given six to 12 months after the first-;can be given to children as young as nine. Teens older than 15 and men and women need three doses of the vaccine to develop an immunity against HPV.

“Pre-teens have a more robust response to the vaccine and generate enough antibodies to protect against HPV after two immunizations, whereas older kids and adults need three doses to get the same immune response,” said Truehart. Another reason not to delay getting the HPV vaccine: an older teen may not want to wait six months or more to be fully immunized against HPV once he or she is on the verge of becoming sexually active. “It’s important for kids to be immunized before they are exposed to HPV,” Truehart said.

Not just for girls
When the U.S. Food and Drug Administration approved the HPV vaccine in 2006, it was recommended for girls and women to protect against cervical cancer. Three years later, the vaccine was approved for boys and men, based on evidence that males are also susceptible to HPV-related cancers. “Cancers caused by HPV affect women and men in equal numbers,” said Loberg. “Each year, there are approximately 10,800 cases of cervical cancer diagnosed in women, and 9,600 cases of head and neck cancer diagnosed in men.” And while there is a screening test for cervical cancer to catch and treat it early, there are no such screening tests for any of the other HPV-related cancers. And because most HPV infections are asymptomatic, people may be unwittingly transmitting the infection to their sexual partners.

HPV also causes genital warts which, although not harmful in most people, can be embarrassing and unsightly. In some cases, however, genital warts can be extremely painful and may even require surgery to remove them. For people with autoimmune disorders or who take medications that compromise their immune system, genital warts can be very difficult to manage, said Loberg. Out of more than 150 strains of HPV, the vaccine targets the most prevalent and harmful ones: two strains that cause genital warts and seven strains that cause various types of cancer.

No serious side effects
Despite HPV being the most common sexually transmitted infection, HPV-related cancers are relatively uncommon because in about 90% of people exposed to HPV, their immune systems clear the virus from their bodies before it causes cancer or precancer. “But we don’t know which individuals will develop a persistent infection, so why take that gamble when cancer can be the consequence?” said Loberg.

When parents ask whether the HPV vaccine is safe, Loberg’s ready answer is that “it’s incredibly safe.” More than 270 million doses of the HPV vaccine have been distributed worldwide since 2006, and there have been no serious side effects. One study that examined data from more than 56 million doses of HPV vaccine administered in the U.S. found that some girls became dizzy or fainted 15 minutes after receiving the vaccine. “That is the only side effect that we see,” other than mild side effects typical of other vaccines, such as fever, headache, and pain and redness at the injection site, said Loberg.

Pediatricians and primary care providers should be recommending the HPV vaccine for children, but if not, parents should bring it up.

“There is absolutely no downside to getting the HPV vaccine, and the upside is preventing your child from getting a deadly or disfiguring cancer,” she said.

January, 2020|Oral Cancer News|

How Marijuana Accelerates Growth of HPV-related Head and Neck Cancer Identified

University of California San Diego School of Medicine researchers have identified the molecular mechanism activated by the presence of tetrahydrocannabinol (THC) — the ingredient that causes people to feel the euphoria or “high” associated with cannabis — in the bloodstream that accelerates cancer growth in patients with human papillomavirus (HPV)-positive head and neck squamous cell carcinoma.

“HPV-related head and neck cancer is one of the fastest growing cancers in the United States. While at the same time, exposure to marijuana is accelerating. This is a huge public health problem,” said Joseph A. Califano III, MD, senior author and professor and vice chief of the Division of Otolaryngology in the Department of Surgery at UC San Diego School of Medicine.

Head and neck squamous cell carcinoma is the sixth most common cancer worldwide. These cancers begin in the cells that line the mucous membranes inside the mouth, nose and throat. Approximately 30 percent of cases of this disease are related to HPV infection, and it is these cases, in particular that are on the rise. Califano suggested increased marijuana use may be a driving factor.

Previous studies have linked daily marijuana exposure to an increased prevalence of HPV-related throat cancer. However, a mechanism linking cannabis exposure to increased growth of the cancer was unknown.

Reporting in the January 13, 2020 online edition of Clinical Cancer Research, a journal of the American Association for Cancer Research, researchers outline how the presence of THC in the bloodstream activates the p38 MAPK pathway, which controls programed cell death called apoptosis. When activated, p38 MAPK prevents apoptosis from occurring, thus allowing cancer cells to grow uncontrollably.

Working with Chao Liu, MD, visiting scientist at UC San Diego and a physician at China’s Central South University, and other colleagues, Califano and team used animal and human cell lines to show that THC turns p38 MAPK on and were able to stop the growth of HPV-positive head and neck cancer by turning off the pathway.

The team then analyzed blood samples from patients with HPV-related throat cancer who had their genomes comprehensively mapped to define activated gene pathways. Similar to the cell lines, the blood samples showed p38 MAPK activation and loss of apoptosis in tumors from patients with THC in their blood.

The authors said studies and public opinion suggestions that THC and other cannabis products have cancer-fighting properties need additional, more critical evaluation. Past studies showing anticancer effects of THC and other cannabinoids often used levels of THC higher than those found with recreational use, but doses used recreationally clearly activate a cancer-causing pathway, said Califano.

“We now have convincing scientific evidence that daily marijuana use can drive tumor growth in HPV-related head and neck cancer,” said Califano. “Marijuana and other cannabis products are often considered benign, but it is important to note that all drugs that have benefits can also have drawbacks. This is a cautionary tale.”

According to the Centers for Disease Control and Prevention (CDC), HPV infections are responsible for approximately 35,000 new cancer diagnoses each year in the United States. Infection is so common that nearly all men and women will get at least one type of HPV at some point in their lives. Most clear up on their own, without the person ever knowing they’ve had it.

Several vaccines are available that can prevent the majority of HPV-related cancers. The vaccines work best when they are given before a person is exposed to the virus. The CDC recommends vaccinating boys and girls age 11 to 12 years old but it can be administered as early as age 9.

According to the National Institute on Drug Abuse, 15 percent of youth 12 to 17 years old and 47 percent of adults age 26 and older have used or tried marijuana.

Together, a low HPV vaccination rate and an increase in marijuana use among youth has the makings of a storm, said Califano, physician-in-chief and director of the Head and Neck Cancer Center at Moores Cancer Center at UC San Diego Health.

Moores Cancer Center is one of only 51 National Cancer Institute-designated Comprehensive Cancer Centers in the country and the only such center in San Diego County.

Treatment options for patients with early- or late-stage head and neck cancers include minimally invasive surgery, reconstruction and rehabilitation, proton therapy and other radiation therapy, innovative clinical trials and targeted therapy, including immunotherapy.

The Head and Neck Cancer Center provides comprehensive care that includes counseling, education and support groups, nutrition, dental rehabilitation, speech and language therapy and social workers to help patients through every step of the process beginning with diagnosis to support lifelong wellness.

Califano and team are now looking at whether cannabidiol, or CBD, has a similar effect to THC. CBD is another major chemical compound found in marijuana, but does not produce the “high” and is now commonly used in various over-the-counter products, such as lotions, ointments and edibles.

In addition, the team is investigating whether p38 MAPK can be targeted with drugs to stop HPV-related head and neck cancer from growing.

Co-authors include: Chao Liu, Sayed Sadat, Koji Ebisumoto, Akihiro Sakai, Bharat Panuganti, Shuling Ren, Yusuke Goto, Sunny Haft, Takahito Fukusumi, Mizuo Ando, Yuki Saito, Pablo Tamayo, Huwate Yeerna, William Kim, Jacqueline Hubbard, Andrew Sharabi and J. Silvio Gutkind from UC San Diego; and Theresa Guo from Johns Hopkins Medical Institutions.

Funding for this research came, in part, from the National Institute of Dental and Craniofacial Research and National Institute of Health (R01 DE023347, U01CA217885, R01HG009285, R01CA121941 and P30CA023100).

January, 2020|Oral Cancer News|

Late stage head and neck cancer in the U.S. sees increasing incidence

Source: www.cancernetwork.com
Author: Hannah Slater

A study released in Cancer indicates that there is an increasing incidence of late stage head and neck cancer (HNC) in the U.S., mostly due to an increasing incidence of oropharyngeal cancer, most likely due to HPV-related disease in patients diagnosed at stage IVC.1

Blacks, males, those who are underinsured or uninsured, and those who are unmarried tend to fare worse than others. The presented research highlights the need for continuous public health efforts toward the early detection of HNC.

In this cohort of 57,118 patients with stage IV HNC, the age-adjusted rates for stage IV HNC significantly increased by 26.1% (6.11 per 100,000 person-years in 2004 to 7.70 per 100,000 person-years in 2015). Despite a decreasing overall incidence of stage IV HNC in black patients (adjusted OR, 1.28; 95% CI, 1.22-1.34), they along with males (adjusted OR, 3.95; 95% CI, 3.80-4.11) had significantly increased risks of being diagnosed with late-stage HNC.

“In the absence of a mortality benefit for asymptomatic mass screenings, as per the U.S. Preventive Services Task Force oral cancer screening guideline, it is critical that there is sustained public awareness and education regarding the early detection of HNC, and prevention through cancer risk mitigation practices,” the researchers wrote.

Although black males had the highest risk of being diagnosed, the most significant change in annual incidence patterns was driven by white males (annual percent changes, 3.13; P < .01). A significant increase in incidence occurred in the population >50 years, with males tending to be younger at the time of diagnosis than females.

Of all primary tumor sites, the oropharynx was the most likely site for a late-stage diagnosis. The incidence of oropharyngeal cancer has increased dramatically in the U.S. within the last 40 years and is predominantly experienced by white males. Approximately 75% of cases of oropharyngeal cancer are associated with human papillomavirus (HPV), and these tumors often present with small primary tumors and larger cystic regional lymph node metastases as the first notable symptom.

Although patients with oropharyngeal cancer typically have a better prognosis, they also remain at risk of having positive lymph nodes and developing distant metastasis. Research indicated that the oropharynx, an HPV-related site, was the only site to experience a significant increase in the incidence of metastatic stage IV disease.

“If rates of true late-stage HNC continue to rise, it remains paramount to identify those patients who are at risk of potentially worse prognoses when HPV status is unknown,” the researchers wrote.

Stage IV was defined using the American Joint Committee on Cancer (AJCC) sixth edition stage classification as stages IVA, IVB, IVC, and IV not otherwise specified. With recent changes in AJCC staging, future studies are warranted to describe incidence trends based on new staging guidelines.

According to the CDC, HPV is so common that nearly all sexually active men and women get the virus at some point in their lives. Oropharyngeal cancers have traditionally been caused by tobacco and alcohol; however recent studies have suggested that about 70% of cancers of the oropharynx may be linked to HPV.2

References:
1. Thompson-Harvey A, Yetukuri M, Hansen AR, et al. Rising Incidence of Late-Stage Head and Neck Cancer in the United States. Cancer. doi:10.1002/cncr.32583.
2. CDC. Human Papillomavirus (HPV) Statistics. CDC website. cdc.gov/std/hpv/stats.htm. Published January 4, 2017. Accessed November 21, 2019.

November, 2019|Oral Cancer News|