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).

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March, 2020|Oral Cancer News|

Okayama University Research: disrupting blood supply to tumors as a new strategy to treat oral cancer

Source: www.prnewswire.com
Author: press release provided by Okayama University

Researchers at Okayama University have recently published a study in Cells in which they reduced the size of oral cancer tumors by damaging the blood vessels surrounding the tumor cells.

Cancer cells have ingenious mechanisms of survival within the body. One strategy they adopt is developing a network of blood vessels around themselves as a source of blood supply. Scientists have long been investigating ways to prevent this blood flow to cancer cells. CXCR4 is a protein known to be closely involved with tumor growth. However, its exact role in tumor progression is unclear. A research team led by Assistant Professor KAWAI Hotaka and YOSHIDA Saori (graduate student, D.D.S.), Assistant Professor EGUCHI Takanori at Okayama University has now shown that CXCR4 is the main culprit maintaining the arrangement of tumor blood vessels.

Firstly they found, immunohistochemistry on human clinical specimens revealed that tumor vessels expressed CXCR4 in human oral cancer specimens. The next question to arise was whether the CXCR4-rich blood vessels were promoting tumor growth. In order to investigate this further, the oral cancer cells were transplanted into mice. Once the tumor grew in mice body, they were given AMD3100—a drug that antagonises CXCR4. When the tumors were subsequently observed under a microscope, several areas were found to necrotic. A characteristic pattern of necrosis was observed in which the tumor tissue that were at a distance away from the blood vessel was necrotic, leaving the tumor tissue close to the periphery of the blood vessel. This randomized pattern of tumor cell death was termed ‘tumor angiogenic inhibition triggered necrosis’ (TAITN) by the researchers. The wide area of tumor tissue also showed a severe lack of oxygen which was accompanied by an impairment of angiogenesis. CXCR4 inhibition thus seemed to induce tumor necrosis by damaging the blood vessels and preventing the cells of a healthy oxygen supply.

This study is the first to show the role of CXCR4 in promoting tumor growth by supplying cancer cells with a healthy, organized network of blood vessels. Strategies that can disrupt this network can be explored further as anti-cancer therapies. “CXCR4 plays a crucial role in tumor angiogenesis required for OSCC progression, whereas TAITN induced by CXCR4 antagonism could be an effective anti-angiogenic therapeutic strategy in OSCC treatment,” concludes the team.

Background

CXCR4: CXCR4 is a protein vital in maintaining and growing the cells that produce blood within our body. In fetuses, CXCR4 is also responsible for the formation of certain blood vessels. Incidentally, CXCR4 is also present in various forms of cancers such as breast, liver, and oral cancer. Often, tumors which show the presence of CXCR4 tend to grow faster that those without. Given its link with blood vessels and cancer progression, the research team from Okayama University sought out to investigate whether CXCR4 directly promotes cancer growth by supplying tumors with blood.

Reference

Saori Yoshida, Hotaka Kawai*, Takanori Eguchi*, Shintaro Sukegawa, May Wathone Oo, Chang Anqi, Kiyofumi Takabatake, Keisuke Nakano, Kuniaki Okamoto, Hitoshi Nagatsuka. Tumor Angiogenic Inhibition Triggered Necrosis (TAITN) in Oral Cancer. Cell, 2019, 8(7), 761.

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March, 2020|Oral Cancer News|

Identified: 15 genes that trigger rapid growth of head and neck squamous cell carcinoma

Source: medicalxpress.com
Author: Bob Yirka , Medical Xpress

A team of researchers affiliated with several institutions in Canada has identified 15 tumor suppressor genes that can trigger rapid growth of human head and neck squamous cell carcinoma (HNSCC) when they mutate. In their paper published in the journal Science, the group describes their reverse genetic CRISPR screen, which allowed them to analyze almost 500 long-tail genetic mutations that lead to HNSCC.

HNSCC is the sixth-most common type of human cancer, and sadly, has a low survival rate. As the researchers note, to date, most studies looking into a cure have focused on the few genes that mutate at a very high rate. This has given them a high profile. But there is another class of slower mutating gene that can lead to tumors in low numbers of patients. Prior research has shown that there are hundreds of these so called “long tail” genes, many of which have not been identified. In this new effort, the researchers used a reverse genetic CRISPR screen that allowed them to identify 15 of them.

The work focused on tumor suppressor genes that regulate cell division. When something goes wrong with them, such as a mutation, they lose their function and thus cannot prevent the cells they were regulating from mutating out of control. More specifically, the team focused their attention on the genes in cells that are part of the notch signaling pathway—in particular, those cells that develop into HNSCC tumors. All mammals have four kinds of notch receptors, which are used for communications between cells. The team carried out in vivo CRISPR screening on 484 long-tail gene mutations that had triggered the development of tumors in mice and identified 15 tumor suppressor genes. They then looked for the same types of mutations in human long-tail mutations and were able to calculate percentages for each.

The researchers conclude that 67 percent of human HNSCC cases occur along the notch signaling pathway, which suggests notch inactivation is a distinguishing characteristic of HNSCC.

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March, 2020|Oral Cancer News|

Gabapentin shows efficacy as opioid alternative for patients with head and neck cancer

Source: www.healio.com
Author: Jennifer Byrne

For many patients with head and neck cancer, treatment-associated oral mucositis is a source of severe pain. Managing this pain is a priority for physicians and interdisciplinary care teams.

Although opioid painkillers historically have been used for this purpose, researchers at Roswell Park Comprehensive Cancer Center investigated the use of gabapentin, a drug used to alleviate nerve pain, as an alternative to narcotics for this patient population.

“Virtually all patients will require some type of pain relief or analgesic medication during the course of chemotherapy and radiation,” study author Anurag K. Singh, MD, professor of oncology and director of radiation research at Roswell Park, told Healio. “We’ve been studying better ways to improve pain control in this population because standard narcotics just don’t work that well. Patients tend to use a lot and they still experience pain, but they are sleepier.”

A dose-dependent effect
In their study, published in Cancer, Singh and colleagues randomly assigned 60 patients with head and neck squamous cell carcinoma to one of two treatment regimens: high-dose gabapentin (2,700 mg daily), progressing sequentially to hydrocodone-acetaminophen and fentanyl when needed (n = 31), or low-dose gabapentin (900 mg daily) progressing to methadone as needed (n = 29).

Safety and toxicity served as the study’s primary endpoints. Pain, opioid requirement and quality of life served as secondary endpoints.

Results showed no difference in pain between the treatment groups, but more patients in the high-dose gabapentin group did not need an opioid while receiving treatment (42% vs. 7%; P = .002). Patients whose treatment progressed to methadone rather than hydrocodone and fentanyl had significantly better quality-of-life outcomes in terms of general health (P = .05), physical functioning (P = .04) role functioning (P = .01) and social functioning (P = .01).

“The bottom line is there was a dose-dependent effect of gabapentin,” Singh told Healio. “When you go from 7% in the lower-dose arm, or 0% if you weren’t giving gabapentin at all, to 42% in the higher-dose arm, that’s a really obvious difference.”

‘Potential arrow in our quiver’
The team at Roswell Park has begun using gabapentin as a first-line approach to pain for patients with head and neck cancer, Singh said.

“We use even higher-dose gabapentin now. We go up to 3,600 mg and follow it with methadone when needed,” he told Healio. “We’re having excellent results. Currently, we’re studying whether we can add something to the gabapentin to get narcotics even further out of the equation.”

Singh and study first author Gregory Hermann, MD, MPH, resident physician in radiation medicine at Roswell Park, have started to evaluate use of the antidepressant venlafaxine (Effexor, Pfizer), which was shown in a study conducted in Europe to enhance the effects of gabapentin.

“Venlafaxine is an SNRI [serotonin-norepinephrine reuptake inhibitor] that is similar to other drugs like duloxetine (Cymbalta, Eli Lilly) that have been used for neuropathic pain in diabetes. It’s a very common medication that is used in primary care,” Hermann told Healio. “At the end of the study, we’ll be able to say whether 3,600 mg is more effective than 2,700 mg and whether venlafaxine adds anything.”

Although opioid painkillers are known for their addictive potential, opioid abuse is less likely among patients with head and neck cancer, provided they are used properly, according to Heath Skinner, MD, PhD, associate professor of radiation oncology at UPMC Hillman Cancer Center. improve significantly within a few weeks of treatment completion,” Skinner told Healio. “In that situation, the goal is to manage pain to allow for eating and drinking as much as possible. Once the acute event leading to the pain is at least partially resolved, we start to wean those medications down. So, in the acute setting, I think these medications have a very limited addiction potential.”

However, if improperly prescribed for long-term use, opioid painkillers could become addictive, Skinner said. Moreover, narcotic painkillers are associated with significant toxicities for an already sick population.

“Constipation is a common effect with opioids and can be particularly challenging for [patients with head and neck cancer] because they’re not drinking a lot of fluids or eating much food,” Skinner told Healio. “That could exacerbate a problem known to happen with narcotic-based pain medications.”

Skinner said gabapentin is a promising alternative to opioids that is readily accessible to clinicians.

“It’s available in the setting of pain control and easily prescribed,” he said. “It’s not something that’s proprietary that a clinician couldn’t acquire. It’s nice to have another potential arrow in our quiver.” – by Jennifer Byrne

Reference:
Hermann GM, et al. Cancer. 2020;doi:10.1002/cncr.32676,

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March, 2020|Oral Cancer News|

Increasing ion channel function in cancer T cells could be new immunotherapy

Source: www.drugtargetreview.com
Author: Ameet Chimote et al.

A previously unknown T cell mechanism that could explain the reason behind decreased immune function in cancer patients has been discovered. According to the researchers, their finding may present a new immunotherapeutic target for patients with head and neck cancers.

The study, conducted at the University of Cincinnati (UC), US, revealed that a reduced interaction between a molecule called calmodulin and the ion channel KCa3.1 in the immune cells of cancer patients plays an important role in the limited function of these cells. The team performed experiments on cytotoxic T cells taken from the blood of patients with head and neck cancer.

“Cytotoxic T cells are like the soldiers of our immune system and are our body’s first line of defence against cancerous tumours,” said first author Ameet Chimote. “These cytotoxic T cells are expected to penetrate the solid tumours by migrating within the tumour mass and then secreting chemicals called cytokines to kill these tumour cells. Sadly, for some reason, these cells do not function properly in patients with cancer and they do not penetrate the tumours and attack the tumour cells, causing the cancerous tumours to grow uncontrollably.”

Lead researcher Professor Laura Conforti, explained: “Identifying the mechanism of this underlying dysfunction can help us identify molecules that we can target with drugs and ultimately restore the ability of these cells to enter and kill the tumours.” Molecules, known as ion channels, are present in the T-cell membranes and are essential for their function.

“In this study, we were able to show that the function of these channels in cells from cancer patients is decreased which results in a decreased T-cell accumulation in solid tumours,” Conforti said.

These types of channels require the signalling molecule calmodulin to bind to them in order to function to their full capacity; this is needed even more in cancer T cells. Using several intricate microscopy imaging techniques on cells isolated from the blood of cancer patients, the team found out that, when compared to T cells from healthy individuals, the cancer T cells have fewer calmodulin molecules in their membranes.

“This would mean that there is less calmodulin binding to the channels in the T cells from cancer patients,” Conforti said. “As previously stated, the channels do not function if the calmodulin does not bind to them. Thus, the decreased calmodulin binding in T cells from cancer patients results in decreased function and leads to reduced tumour infiltration and killing of the cancer cells.”

“We observed that if we increase the function of these channels by drugs that enhance their activity, the cancer patients’ T cells can penetrate the tumours better and also produce increased cytokines which can kill tumour cells,” Chimote explained. “These are exciting findings that could lead to additional treatments for patients with cancer.”

“These findings strengthen the therapeutic potentials of [these] activators, which could restore cytotoxic T-cell functionality and can ultimately lead to additional immunotherapeutic options for patients with cancer,” Conforti conlcuded.

The study was published in Frontiers in Pharmacology.

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March, 2020|Oral Cancer News|

Another vaping hazard: less-healthy mouths

Source: www.usnews.com/
Author: Serena Gordon, HealthDay Reporter

Your lungs might not be your only concern if you’re trying electronic cigarettes — your mouth may pay the price, too. Vaping alters the natural bacteria found in the mouth, leaving you more vulnerable to oral infections and inflammation, a new study reports.

The researchers said this study is the first to show that vaping can alter the natural balance of beneficial bacteria (microbiome) in the mouth, adding to the list of potential health effects associated with e-cigarette use.

“Cells that are exposed to e-cigarettes are more susceptible to infections,” said the study’s senior author, Deepak Saxena. He’s a professor of basic science and craniofacial biology at NYU College of Dentistry in New York City.

Saxena said that e-cigarettes also lead to increased inflammation, which harms oral health. And once someone develops inflammation, it’s possible to develop white patches in the mouth called leukoplakia that sometimes develop into cancer. However, this study doesn’t have enough long-term evidence to show whether or not these changes could lead to oral cancers in the future, Saxena said.

“Our study is just one piece of this big puzzle on e-cigarettes, and I would advise people to not use them. If you have not started, don’t start. Nicotine is highly addictive,” he said.

A U.S. Centers for Disease Control and Prevention report from November suggested that as many as one out of every five U.S. high school students had vaped in the last month. That’s especially concerning since more than 2,500 Americans have been hospitalized with lung injuries traced back to e-cigarette use. An additive sometimes used when people vape is suspected as a trigger for these injuries. Fifty-four people have died as a result.

People who smoke traditional tobacco cigarettes are known to have a higher risk of gum disease and oral infections. Tobacco causes changes in the mouth’s usual environment that dampen the immune system response and let bad bacteria flourish, the researchers explained.

E-cigarettes have been considered less harmful, but there hasn’t been a lot of research, particularly long-term studies on the new devices.

For the new study, the research team recruited 119 participants, including roughly equal numbers of people who didn’t smoke or vape, people who smoked tobacco cigarettes, and those who had only used e-cigarettes. The researchers performed oral exams and collected saliva samples to test for the bacteria living in the participants’ mouths.

Almost three-quarters of tobacco smokers showed signs of gum disease or infection. Forty-three percent of e-cigarettes users also showed signs of these problems. Only 28% of the nonsmokers had signs of gum disease or infection.

When they tested for bacteria, the researchers found different types of predominant bacteria in the three groups.

“We found there is a shift in the microbiome of e-cigarette users, making it much closer to that of regular cigarette smokers,” Saxena said.

Co-author Xin Li, an associate professor at NYU College of Dentistry, noted that the researchers can’t say if e-cigarettes are more dangerous for oral health than traditional tobacco cigarettes.

“We saw a similar trend to inflammation and periodontitis (a serious gum infection), but I don’t think we can draw any conclusions about whether e-cigarettes are more harmful,” she said.

If you vape and have concerns about these potential changes, Saxena suggested taking greater care with your oral health and perhaps seeing your dentist more frequently. Li said maybe probiotics can help restore the microbiome in the mouth. But both noted these steps haven’t been studied yet.

Li said if you are using e-cigarettes to help with quitting traditional tobacco cigarettes, try to use e-cigarettes for the shortest time you can. Plan on how you’ll cut back. Don’t plan to use e-cigarettes indefinitely, she advised.

Ronald Burakoff is chairman of dental medicine at Long Island Jewish Medical Center and North Shore University Hospital in New York. He said the study’s findings make sense.

“This article describes in detail some of the adverse outcomes associated with [e-cigarette] usage. Firstly, it increases the amount of bacteria in the mouth; secondly, it promotes inflammation of the gums,” Burakoff said. He added that these changes could lead to an increased risk of infection.

Note: The study was published online Feb. 26 in iScience.

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February, 2020|Oral Cancer News|

What’s coming down the pike in the dental profession?

Source: www.dentistryiq.com
Author: Richard H. Nagelberg, DDS

A plethora of dental research is underway in the US as well as globally. Some of these advancements will come to fruition and be commercially available, and some will die on the vine. There are innovations in essentially every dental discipline, with breakthroughs that have the potential to enhance oral health in ways we couldn’t imagine in the past.

The impact of artificial intelligence (AI) will increase in the future. AI is already at work in hospitals to diagnose cancer and anticipate trends in health care. AI will have a significant effect in the dental profession on a daily basis, from evaluating images for pathology, to prosthetics and systemic care, among many others. AI promises to increase efficiency in dental practice by facilitating faster diagnosis, predictive analytics, and autocharting.

Other areas of research and development include gene therapy and stem cells. Research is underway using gene therapy to restore salivary function in patients who have undergone radiation treatment, which could be a tremendous improvement in health for these individuals. The negative impact of dry mouth extends far beyond the discomfort associated with inadequate or complete lack of saliva. It has a significant effect on the quality of life of the individual and the health of the oral cavity. The ability to restore salivary function could be life-changing for many people.

Other initiatives involve transformative research in periodontics, specifically agents operating on the host response and others applied to the diseased periodontal pockets. Some of the research on host-response therapies involves agents that repair the immune system dysfunction responsible for tissue degeneration. This is accomplished by using minute quantities of an agent that creates a gradient, resulting in the mobilization of regulatory cells that dampen down the inflammatory response, which is responsible for the tissue destruction that accompanies periodontal disease.

Some of the research focused on the clinical application of agents into periodontal pockets does not involve antimicrobial therapies, but rather are regenerative in nature. Preparation of the affected area is simple and quick, followed by application of the regenerative agent. Clinical trials have demonstrated significant pocket depth reduction and bone regeneration. If these results are consistent and reproducible, a complete paradigm shift in the treatment of periodontitis could occur—one that is essentially noninvasive, quick, and inexpensive.

There are a number of disruptive technologies in various stages of development that will dramatically change the manner in which we practice dentistry. Some of these changes will mirror developments in the medical profession, such as gene therapy and influencing the immunoinflammatory system to reduce tissue damage, which ultimately benefits the individual’s oral and overall health.

Note:
This article originally appeared in Breakthrough Clinical, a clinical specialties newsletter from Dental Economics and DentistryIQ.

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February, 2020|Oral Cancer News|

Absent p53, oral cancers recruit and reprogram nerves to fuel tumor growth

Source: medicalxpress.com
Author: by University of Texas M. D. Anderson Cancer Center

Loss of an important tumor-suppressing gene allows head and neck cancer to spin off signals to nearby nerves, changing their function and recruiting them to the tumor, where they fuel growth and cancer progression, researchers from The University of Texas MD Anderson Cancer Center report in the journal Nature today.

By cracking the mechanism that launches neuronal invasion of tumors, a known marker of poor prognosis for patients, the team has uncovered possible avenues to block the process, including the use of drugs commonly used to treat blood pressure and irregular heartbeat.

“Tons of studies show that patients who have lots of nerves in their tumor are doing worse—recurrence rates are higher, survival is shorter,” says co-first author Moran Amit, M.D., Ph.D., assistant professor of Head and Neck Surgery. “Nerve endings found in surgically removed tumors can’t be easily characterized or tracked back to their source, so it’s been a neglected field, a neglected hallmark of cancer.”

“When surgeons remove head and neck cancers and find a high degree of nerve invasion, post-surgical radiation sometimes is effective,” said co-senior author Jeffrey Myers, M.D., Ph.D., chair of Head and Neck Surgery. “But we really haven’t understood whether the tumor was growing into the nerves or the nerve growing into the tumor and what signaling drove those interactions.”

Co-senior author George Calin, M.D., Ph.D., professor of Experimental Therapeutics and an expert on non-coding RNAs added that the paper “puts together for the first time the mechanism of involvement of neurons in tumor generation, a new hallmark of cancer.”

The team found that the neurons that invade the tumor are adrenergic nerves, which are involved in stress response. These nerves’ neurotransmitters—adrenaline (epinephrine) and noradrenaline (norepinephrine) – are susceptible to drugs known as alpha and beta blockers, long used to treat high blood pressure and irregular heartbeats.

In the study, mice with oral cancer treated with the adrenergic blocker carvedilol had sharply lower tumor growth and cancer cell proliferation. Myers says the team is working to develop clinical trials of adrenergic blockers, most likely in combination with other drugs.

“We used to think that nerves are just randomly growing into the tumor, and that’s completely wrong,” Amit says.

Loss of p53 flips a microRNA switch to re-program neurons
Damage to the p53 gene is a major characteristic of head and neck cancers. A tumor-suppressing master transcriptional gene that governs the expression of many other genes, p53 is also mutated in a variety of cancers.

The team found high density of neurons in p53-deficient mouse models and human xenograft tumors of oral cavity squamous cell carcinoma (OCSCC) as well as increased neural growth in clusters of nerves exposed to p53-deficient OCSCC.

The researchers also discovered that oral cancer communicates with nerves by launching extracellular vesicles—membrane balls that carry various molecules—packed with microRNAs to connect with the nerves. The miRNA cargo varied depending on p53 status of the tumors.

“When you have intact p53, you have specific types of microRNAs that keep neurons in a quiescent state,” Amit says. “Once you lose p53, the micro RNA population within the exosomes changes and then you get positive signals to induce nerve growth.”

Investigators identified adrenergic nerves extending into the tumors and suspected they were extensions of pre-existing nerves. However, when they cut adrenergic nerves before inducing tumors in mice, adrenergic nerves still appeared in the tumor and the tumors still grew.

Subsequent experiments showed the miRNAs in vesicles from p53-deficient tumors were connecting instead with existing sensory nerves, a different nerve type, and actually changing them into the adrenergic type. These neo-adrenergic nerves then invaded the tumor.

To confirm this finding, they cut sensory nerves ahead of inducing p53-deficient tumors in mice. Without the sensory nerve targets for the vesicles, the tumor shrank.

Impact of adrenergic nerve density on patients
To validate the impact of their findings on people with OCSCC, the researchers analyzed the presence of adrenergic nerves in the tumors of 70 patients who were treated at MD Anderson. Adrenergic nerve density in the tumors was associated with lower recurrence-free survival and overall survival.

The statistical significance of the adrenergic nerve densities held up in multivariable analysis after adjustment for other variables, such as age, sex, cancer stage, surgical margin status, overall neuronal invasion and treatment type. They suggest nerve density measurements merit exploration as a predictive marker of oral cancer aggressiveness. Myers, Calin, Amit and colleagues believe the paper opens up a new area for cancer researchers.

“Neurons control everything that we do in everyday life,” Amit says. “They control our voluntary and involuntary bodily functions, so it’s intuitive that they are involved in cancer.”

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February, 2020|Oral Cancer News|

FDA grants fast track designation to NBTXR3 in locally advanced head and neck cancers

Source: www.targetedonc.com
Author: Nichole Tucker

An FDA Fast Track Designation was granted to the first-in-class radioenhancer NBTXR3 with or without cetuximab (Erbitux) for the treatment of patients with locally advanced head and neck squamous cell cancer who are not eligible for platinum-based chemotherapy, according to a press release from Nanobiotix.1

NBTXR3 showed preliminary signals of antitumor activity in this patient population in a phase I study of 12 patients with advanced-stage head and neck squamous cell carcinoma (HNSCC). Specifically, 10 of the 11 evaluable patients had a complete response (CR) or a partial response to treatment, which included 2 CRs at dose levels ≤10% and 5 CRs at dose levels >10%.2

Treatment with NBTXR3 was also found to be safe and tolerable in patients with HNSCC. There were no serious adverse events or dose-limiting toxicities (DLTs) observed, which allowed patients to continue with their treatment as planned. The adverse events found to be related to injection with NBTXR3 included grade 1/2 injection pain and tumor hemorrhage.

Patients in the study received either a single intratumor injection or single-arterial injection of NBTXR3 on day 1 followed by intensity-modulated radiation therapy 2 hours later, which lasted for up to 7 weeks. Radiotherapy was continued in all patients unless their tumor did not shrink by 50% of the baseline size. Those patients who did achieve the tumor shrinkage goals then received salvage tumor surgery.

The primary end point of the study was the determination of the recommended dose of the drug and early dose-limiting toxicities. Secondarily, the investigators evaluated safety and tolerability, objective response rate, local progression-free survival, progression-free survival, kinetics profile, and the feasibility of local administration of NBTXR3.

Patients aged 70 years or older who were intolerant to cisplatin or cetuximab or that could not receive the combination of chemoradiation were eligible for treatment in the study. Patients were required to have histologically or cytologically confirmed squamous cell carcinoma of the oral cavity or oropharynx; have a T3 or T4 primary tumor or stage III or IVA disease; be clinically eligible for intra-arterial or intratumor implantation by injection; have a Karnofsky performance status ≥70; and have adequate bone marrow, kidney, and liver function.

The study excluded patients who had prior radiotherapy; tumor-related dyspnea; prior or concurrent non-head and neck malignancies, excluding adequately treated basal or squamous cell cancer of the skin, and in situ cervical cancer; concurrent treatment with any other anticancer therapy; tumor-related dyspnea; tumor ulceration which implies vascular risk; non-measurable disease; and those with infections and illnesses that may have interfered with treatment.

The data from this trial are part of a proof-of-concept for launching a phase III study in which NBTXR3 will undergo further assessment for the treatment of head and neck cancers.3

References
1. Nanobiotix announces fast track designation granted by US FDA for investigation of first-in-class nbtxr3 in head and neck cancer [news release]. Cambridge, Massachusetts: Nanobiotix; February 10, 2020. https://bit.ly/2vpwDQU. Accessed February 10, 2020.
2. Le Tourneau C, Calugaru V, Jouffroy T, et al. A phase 1 trial of NBTXR3 nanoparticles activated by intensity-modulated radiation therapy (IMRT) in the treatment of advanced-stage head and neck squamous cell carcinoma (HNSCC). J Clin Oncol. 2017;35(suppl 5;abstr 6080). doi: 10.1200/JCO.2017.35.15_suppl.6080.
3. Nanobiotix announces plan for global phase III head and neck cancer registration trial along with overall development update [news release]. Cambridge, Massachusetts: Nanobiotix; January 7, 2020. https://bwnews.pr/2Hczpfc. Accessed February 10, 2020.

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February, 2020|Oral Cancer News|

How Can Dental Practitioners Join the Fight Against HPV-Associated Oropharyngeal Cancer?

Source: Aegis Dental Network
Date: February 2020, Volume 41, Issue 2
Authors: Jack Dillenberg, DDS, MPH; A. Ross Kerr, DDS, MSD; Alexis Koskan, PhD; Seena Patel, DMD, MPH; Mai-Ly Duong, DMD, MPH, MAEdAeg

Dr. Dillenberg

The entire dental team has the responsibility of impacting the overall health of their patients. This becomes even more relevant with the realization that up to 27 million people each year visit a dentist and not a physician, thus providing a special opportunity for primary care issues to be addressed in the dental setting.

One such opportunity is oropharyngeal cancer (OPC) prevention and control. An estimated 51,540 new cases of oral and pharyngeal cancer occurred in 2019, with a 5-year relative survival rate of 65%.1 Of these, it is estimated that 19,000 are human papilloma virus (HPV)-associated OPC, which is the only cancer that has increased in prevalence in the past 5 years, and that these numbers will continue to rise.1

Whereas the use of alcohol and tobacco were once the leading causes of OPC, the emergence of HPV infection as the main cause of OPC has changed everything. Infection with HPV (particularly HPV type 16) is transmitted primarily through sexual contact and is a vaccine-preventable virus. HPV is the most common sexually transmitted disease and can be spread even when someone infected with this virus has no signs or symptoms. Therefore, the dental team should be aware of this serious emerging cancer, be able to educate patients about risk factors, and engage in preventive activities, such as opportunistic screening and detection, and the promotion of vaccination.

Dr. Kerr

Dental clinicians should be able to recognize the presenting signs and symptoms of HPV-associated OPC (HPV-OPC). The oropharynx encompasses the soft palate, fauces, tonsillar fossae and palatine tonsils, posterior pharyngeal wall, and the base of tongue/lingual tonsils. The most common presenting symptom of a patient who may have a HPV-OPC is a non-painful neck mass.2,3 This occurs in approximately 50% to 70% of patients with OPC, and it corresponds to the spread of the cancer from the primary oropharyngeal site to the regional lymph nodes of the neck. In patients without a neck mass, other symptoms include one or more of the following: sore throat, visible oropharyngeal mass, dysphagia or odynophagia, globus sensation, or otalgia.4

There is insufficient evidence for the US Preventive Services Task Force to recommend specific screening guidelines for the early detection of HPV-OPC. However, standard dental practice dictates that at new patient and recall visits, patients are asked about current symptoms as well as receive a visual and tactile head and neck soft-tissue examination. Palpation with detection of lymphadenopathy that cannot be attributed to a benign cause (such as inflammatory lymph nodes secondary to an odontogenic infection) and/or visualization/palpation of accessible oropharyngeal structures with detection of abnormal lesions or gross asymmetry of tonsillar structures should all raise suspicion for malignancy. Abnormal signs and symptoms should trigger a referral to an expert, ideally an otolaryngologist/head and neck oncologic surgeon.

There is no evidence to support the use of salivary or serum-based screening tests to detect oncogenic HPV genotypes in the general population. Large cohort studies where subjects submit mouthrinse samples demonstrate an approximate prevalence of 1% patients testing positive for HPV 16 infection, the most cancerous of the HPV strains.5 Yet, few of these infections represent persistent infection, and even fewer lead to malignant transformation. Research suggests testing patients who are at higher risk for acquiring persistent HPV 16 infection as a feasible OPC screening strategy in a dental setting.6

Benign HPV-associated lesions (ie, viral papilloma, verruca vulgaris, condyloma acuminatum) involving the oral cavity (and oropharynx) may be detected during examination. Such lesions are typically solitary, exophytic, often pedunculated, pink to white in color, and with a variable surface ranging from papillary (ie, fingerlike projections) to flat. These lesions have no malignant potential, are associated with non-oncogenic HPV genotypes,7 and should be excised.

Dr. Koskan

What is the HPV vaccine? Vaccines that protect against HPV, and therefore HPV-OPC, have been commercially available in the United States since 2006. Currently, healthcare providers administer Gardasil® 9, a vaccine series that protects against nine different HPV genotypes, seven which cause the majority of HPV-related cancers (including OPC) and two that cause genital warts and recurrent respiratory papillomatosis. More specifically, the vaccine protects against HPV type 16, the strain most commonly associated with OPC. Therefore, vaccine uptake and completion is believed to help prevent HPV-OPC.

Whereas the HPV vaccine was once marketed for women, all individuals aged 9 to 26 years should receive the vaccine. Individuals aged 9 to 14 years with healthy immune systems need two doses to complete the series, and persons over age 15 and/or who are immunosuppressed should receive three doses.8 The vaccine is most effective prior to sexual debut. However, even among those previously exposed to HPV strains, the vaccine can protect from future infection from strains in which the individual has not been exposed and from future re-infection from previously exposed HPV strains, thus reducing cancer risk.9

Insurance provides coverage for this otherwise prohibitively expensive vaccine (roughly $230 per dose) series. Some plans provide coverage for adults up to age 45. For this reason, the Centers for Disease Control and Prevention (CDC) recommends shared decision-making with a primary care provider to discuss the vaccine benefits.

The HPV vaccine is safe and effective.10 The most common side effects include mild pain, redness, and, less common, slight swelling at the site of vaccine injection.11 The vaccine is effective in preventing genital warts and infection with the most common cancerous HPV strains.

Drs. Patel and Duong

Oral healthcare providers should be proactive in educating their patients in HPV-OPC prevention, promoting the HPV vaccine, and learning more to reduce the disease’s incidence, as provider recommendation is a vital predictor of HPV vaccine uptake and completion.

First, improving HPV-related health literacy is necessary among dental providers.12-17 Specifically, dental providers having a sound understanding of HPV, its pathophysiology, and its cancer-causing potential is key to educating patients and parents. Second, dental providers need to be well-versed in HPV-associated OPC preventive methods, specifically the HPV vaccine. Most oral health providers still do not know enough about the vaccine, and hence, do not feel comfortable recommending it.18

When discussing the HPV vaccine, it is important to promote it as a cancer prevention tool. It can be likened to other vaccines that have a similar purpose, such as the hepatitis B vaccine, which prevents viral hepatitis and hepatocellular carcinoma. The provider should give a strong recommendation for the vaccine and emphasize that HPV-OPC is a public health epidemic. Communicating the rise in incidence of this disease and the fact that it is caused by a very common infection may help parents understand how critical HPV vaccination is. Alleviating concerns about common myths is also important, such as the vaccine is not only for girls, it does not encourage early sexual debut, and it is not associated with any serious health risks or mortality.

Most practitioners do not feel confident answering patients’ questions about HPV vaccination.19 However, if a trustworthy standard set of talking points were made available, providers are willing to educate their patients about the importance of HPV vaccination and refer patients to medical providers to receive the vaccine.18,19 Further, providers were willing to participate in training programs to promote and administer the HPV vaccine.

Tools are available to improve communication practices about HPV in the dental setting, such as the #HowIRecommend videos posted on the CDC website (cdc.gov). Keeping brochures and educational videos about HPV, HPV-OPC, and the HPV vaccine in the office lobby and patient rooms can help increase knowledge and awareness. Additionally, adding a question on patient intake forms about whether the patient has received HPV vaccine doses allows the provider to more easily start this conversation. Another prime time to recommend this cancer prevention vaccine is during an oral cancer screening.

Conclusion

Dental providers have the unique opportunity to help reduce the incidence of oropharyngeal cancer. Two critical steps can be taken. First, they can work with state and local dental associations to pass regulatory legislation that would allow dentists to administer the HPV vaccine to their patients, as needed. Second, they can educate their patients and patients’ parents that the HPV vaccine is a cancer prevention resource. Enacting these steps may lead to increased HPV vaccine uptake and, in turn, reduced cases of HPV-related oropharyngeal cancer.

About the Authors

Jack Dillenberg, DDS, MPH
Dean Emeritus, Arizona School of Dentistry & Oral Health, A.T. Still University, Mesa, Arizona; The ATSU Center for the Future of the Health Professions

A. Ross Kerr, DDS, MSD
Clinical Professor, Oral and Maxillofacial Pathology, Radiology and Medicine, New York University College of Dentistry, New York, New York

Alexis Koskan, PhD
Assistant Professor, College of Health Solutions, Arizona State University, Phoenix, Arizona

Seena Patel, DMD, MPH
Associate Professor and Associate Director of Oral Medicine, Arizona School of Dentistry & Oral Health, A.T. Still University, Mesa, Arizona; Private Practice, Phoenix, Arizona

Mai-Ly Duong, DMD, MPH, MAEd
Associate Professor and Associate Director of Special Care Dentistry, Arizona School of Dentistry & Oral Health, A.T. Still University, Mesa, Arizona; Private Practice, Phoenix, Arizona

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February, 2020|Oral Cancer News|