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|

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.

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February, 2020|Oral Cancer News|

Botanical drug is shown to help patients with head and neck cancers

Source: newsroom.ucla.edu
Author: Duane Bates, UCLA Research Brief

Findings
In a UCLA-led phase I clinical trial, a new plant-based drug called APG-157 showed signs of helping patients fight oral and oropharyngeal cancers. These cancers are located in the head and the neck.

APG-157 is made up of multiple compounds produced by plants, including curcumin. UCLA Jonsson Comprehensive Cancer Center researchers found that treatment with this botanical drug resulted in high concentrations of curcumin and its byproducts circulating in the blood and absorbed by tumor tissues within three hours after being taken orally.

APG-157 reduced the concentration of cytokines — proteins involved in inflammation — in the saliva when administered to cancer patients. The therapy also reduced the relative abundance of Bacteroides species, a group of gram-negative bacteria. Gram negative refers to a group of dangerous bacteria that have an outer layer which hides them from the immune system. The relative abundance of gram-negative bacteria compared to the presence of other types of bacteria is correlated with oral cancer.

APG-157 also resulted in the expression of genes that are associated with attracting immune system T cells to the tumor area. This therapy could have a beneficial effect when used in combination with immunotherapy drugs that help immune system T cells recognize and kill tumors.

The treatment did not have any adverse effects on the study’s participants.

Background
Cancers of the head and neck account for 4% of all cancers. About 650,000 new cases are reported each year around the world. People with advanced head and neck cancers have a low survival rate and current treatment options such as surgery, radiation and chemotherapy can have adverse effects. Therefore, more effective and less toxic therapies are needed to help improve the quality of life and outcome for those with these cancers.

APG-157 is a botanical drug developed under the FDA’s Botanical Drug Guidance, which includes requirements for production of plant-based therapies that are marketed as prescription medications. The drug is made up of botanical compounds including curcumin from the Curcuma longa plant, which is commonly referred to as turmeric and is a member of the ginger family.

Curcumin is one of the medicinally active or therapeutic molecules that has been tested as a possible treatment to help fight multiple cancers because it is an antioxidant that reduces swelling and inflammation. However, there is poor absorption into the bloodstream when curcumin is taken orally. In this study, UCLA researchers found that when APG-157 is taken through oral mucosal absorption, patients have high levels of curcumin circulating in their blood and absorbed by cancer tissues.

Method
UCLA researchers conducted the study of APG-157 comparing 12 people who had oral and oropharyngeal cancer with a control group of 13 people who did not have cancer. The reason both the people with cancer and without cancer were part of the study was to show that the drug was not toxic to either people with cancer or those without cancer.

The medication was given each hour for three hours and was delivered as a lozenge that slowly dissolved in the mouth. Blood and saliva samples were collected beforehand — each of the three hours the medication was administered — and 24 hours after the last dosage. The medication was given to 12 people (some who had cancer and some who did not) and a placebo was given to 13 people. Blood and electrocardiogram tests did not show increased toxicity in the people who took the active medication in comparison with the people who took the placebo, regardless of whether they had cancer or not.

For the cancer patients who took the medication, there was a decrease in Bacteroides and an increase in T cells in the tumor tissue as compared to cancer patients who took the placebo. Neither the subjects nor the investigators knew whether the drug or a placebo was given when reviewing the blood and saliva test results of the blinded study.

Impact
APG-157 is a botanical drug that has low toxicity. It works effectively to reduce inflammation that contributes to the growth of cancer cells. It also attracts T cells to the tumor micro-environment. When used in combination with immunotherapy drugs, APG-157 might have the ability to make the immune system more effective in attacking head and neck cancers. With potential to inhibit the growth of Bacteroides species, APG-157 could also improve cancer therapy through oral microbial changes.

Authors
Dr. Marilene Wang from UCLA was the corresponding author. Other UCLA authors include: Saroj Basak, Alexander Yoon, Marco Morselli, Chan Jeong, Anela Tosevska, Tien Dong, Hassan Nasser, Venu Lagishetty, Rong Guo, Dipti Sajed, Kym Faull, Jonathan Jacobs, Matteo Pellegrini, Daniel Sanghoon Shin and Eri Srivatsan. Authors from Uniformed Services University of the Health Sciences in Maryland and Aveta Biomics also participated in the study.

Journal
The research is published in CANCER, a journal published by the American Cancer Society.

Funding
Funding for the study was provided by Aveta Biomics.

Disclosures
Authors Parag Mehta, Sharmila Mudgal and Luis Avila are employed by Aveta Biomics. They had no role in the recruitment of people for this study or the collection and analyses of the samples. They, as with all the authors, did not have any information on the subjects, therapy or placebo given until completion of the study.

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February, 2020|Oral Cancer News|

Curcumin has anti-proliferative and pro-apoptotic effects on tongue cancer in vitro: a study with bioinformatics analysis and in vitro experiments

Source: www.dovepress.com
Authors: Chao Ma,1 Zongming Zhuang,1 Qisheng Su,2 Jianfeng He,1 Haoyu Li1

Purpose:
This study focused on the mechanism underlying the therapeutic effect of curcumin against tongue cancer (TC). Accepted for publication in Drug Design, Development and Therapy, Volume 14.

Methods:
Target genes of TC and curcumin were identified, respectively. Three datasets of TC from Gene Expression Omnibus were included, and then the differentially expressed genes were collected. After combing the data from The Cancer Genome Atlas, bioinformatics analyses were performed to investigate hub genes in terms of the functions and correlations. The proliferation and migration of TC cells were evaluated with CCK-8 assay and scratch wound healing assay, respectively. Cell apoptosis was evaluated by TUNEL assay, flow cytometry and Western blot. Cell cycle was determined by flow cytometry.

Results:
In this study, 15 hub genes were identified (TK1, TDRD3, TAGLN2, RNASEH2A, PDE2A, NCF2, MAP3K3, GPX3, GPD1L, GBP1, ENO1, CAT, ALDH6A1, AGPS and ACACB). They were mainly enriched in oxygen-related processes, such as oxidation-reduction process, reactive oxygen species metabolic process, hydrogen peroxide catabolic process, oxidoreductase activity and Peroxisome-related pathway. The expression levels of hub gene mRNAs were positively correlated with each other’s expression levels. None of the hub genes was correlated with prognosis (P > 0.05). Curcumin significantly inhibited CAL 27 cell proliferation and migration (P < 0.05), but significantly promoted cell apoptosis (P < 0.05). Conclusion: Curcumin has potential therapeutic effect on treating TC by suppressing cell proliferation and migration, as well as promoting apoptosis through modulating oxygen-related signaling pathways.

Notes:
1 Department of Ophthalmology, The First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of China;
2 Department of Clinical Laboratory, The First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of China

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February, 2020|Oral Cancer News|

Cancers Caused by HPV Respond Better to Treatment — a New Study Helps Explain Why

Source: Memorial Sloan Kettering Cancer Center
Date: January 20th, 2020
Author: Matthew Tontonoz

Human papillomavirus (HPV) causes several types of cancer, including cervical, anal, and head and neck cancers. People with these tumors are more easily cured with radiation and chemotherapy than people with tumors not caused by HPV. Scientists at Memorial Sloan Kettering now think they understand why.

“We’ve known that HPV-associated cancers respond much better to radiation therapy, but it hasn’t been clear why that is,” says Daniel Higginson, a physician-scientist at MSK. “Our research shows that it’s likely because the virus alters the cells’ normal DNA repair machinery.”

Radiation therapy damages DNA. Cancers caused by HPV are less able to repair this damage and so they die.

The difference in cure rates between HPV-caused and non-HPV-caused cancers is stark: 85% to 90% of patients with HPV-associated oropharyngeal cancer (which affects the middle part of the throat), for example, are cured by radiation and chemotherapy, compared with about 60% of people with non-HPV-caused oropharyngeal cancer.

“We don’t have many biomarkers that predict response to radiation therapy,” says Dr. Higginson. “But HPV is a very good one and is consistent across multiple malignancies.”

What the Virus Does

HPV promotes cancer by inserting pieces of its own DNA into a person’s cells. The DNA pieces trick the human cells into making two distinct proteins that cooperate to turn normal cells cancerous. These proteins (called E6 and E7) disrupt the cells’ machinery for stopping unwanted growth (specifically, two proteins called p53 and Rb).

When this machinery is disabled, the cells begin to divide without restraint. They also tend to accumulate mutations because DNA damage goes unrepaired. Eventually, the cells have enough additional mutations to turn cancerous.

Tricking the cells into dividing repeatedly is advantageous to the virus because this is how HPV reproduces itself; each time a host cell divides it makes more of the virus.

Previous research had pointed to faulty DNA repair as a possible reason why HPV-caused cancers are more sensitive to radiation. But there are several types of DNA repair — which one might be involved was an open question.

Homing in on DNA Repair

To get to the bottom of these questions, the researchers first looked for evidence of different types of DNA repair in more than 10,000 tumors across 32 cancer types in data sets from The Cancer Genome Atlas. They discovered that HPV-caused cancers have DNA changes more characteristic of a repair process called microhomology-mediated end joining (MMEJ). This form of DNA repair is a backup system that comes into play when other repair systems fail, but it is prone to making errors.

The researchers then turned to laboratory experiments. By introducing DNA breaks into HPV-infected cancer cells and measuring how these breaks were repaired, the MSK scientists confirmed that HPV (specifically the E7 protein) suppresses a form of DNA repair called canonical nonhomologous end joining. As a result, the cells become more dependent on MMEJ.

Why might HPV prefer this form of less-than-accurate repair? Some evidence suggests that MMEJ helps the virus integrate its DNA into the host cell’s DNA.

Dr. Higginson says that looking for biomarkers of MMEJ dependence in cancers may help doctors tailor treatments to those who may benefit from them the most. In addition, the findings provide a rationale for exploring ways to block MMEJ factors with drugs in HPV-caused cancers. These results were published October 7, 2019 in the journal Proceedings of the National Academy of Sciences.

Cancers caused by HPV constitute about 4.5% of all solid tumors. A vaccine to prevent infection with the most dangerous HPV strains is available.

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February, 2020|Oral Cancer News|

National Vaccination Program Leads To Marked Reduction In HPV Infections

Source: Forbes
Date: January 28th, 2020
Author: Nina Shapiro

While widespread vaccination continues to be a source of contention in this country and others, one of the newer vaccines has begun to demonstrate remarkable positive impact, which will hopefully become harder and harder to dispute. The HPV vaccine, with trade name GardasilR, is recommended for both boys and girls, ideally sometime between ages 11 and 12 years, given in two doses at a six month interval. It can be given as early as age 9, and as late as age 26. Older adults, even up to age 45, can receive the vaccine, although it is more likely that these adults have already been exposed to the virus, and are less likely to be protected by the vaccine.

The vaccine prevents infection with the human papillomavirus (HPV), which can cause health problems ranging from nuisance-causing warts to cancer-causing lesions of the cervix, throat, and anorectal area. When HPV-related cancers hit Hollywood, with Michael Douglas publicly attributing his throat cancer to HPV, it became clear that this disease can no doubt affect both men and women. When Marcia Cross announced that her anal cancer was due to HPV infection, it raised yet another red flag that HPV can affect the lower gastrointestinal tract, not just the female reproductive tract. Indeed, HPV can affect any of us, at any age, from stem to stern. As I wrote in an earlier Forbes piece, the vaccine to prevent HPV can prevent not only sexually transmitted infections (STI’s) causing genital warts, but it can also prevent cancer.

A lesser known impact of active HPV infection is that the virus can be transmitted from pregnant mother to her fetus via amniotic fluid. The child can later (usually as a toddler) develop warts on the vocal cords, known as recurrent respiratory papillomatosis, or RRP. These warts lead to progressively worsening airway blockage, and even death. And while there are treatments for RRP, there is no cure; only prevention. In another Forbes article, I explain how reduction of HPV infections, thanks to vaccine programs, can reduce the incidence of RRP in the next generation.

A report released this week by Public Health England, published in Health Protection Report, reviewed surveillance data from outcomes of a national HPV vaccination program, which began in 2008. The vaccine is offered to 12-13 year-old males and females, and the report then looked at incidence of HPV infection of the reproductive tract in sexually active 16-24 year-old females. As is the case with many viruses, HPV has many subtypes, some of which are more likely to be associated with aggressive cancers (subtypes 16 and 18 as well as 31, 33, and 45) and others are more likely to be associated with RRP infections and genital warts (subtypes 6 and 11). Until 2012, the bivalent (HPV 16/18) vaccine (CervarixR) was administered as a three-dose regimen. In years since then, the quadrivalent (HPV 16/18/6/11) (GardasilR) has been the standard vaccine administered in the U.K. as well as the U.S. as a two-dose regimen. Cervical cancer is due to HPV 16 or HPV 18 in up to 80% of cancers.

The recent report out of the U.K. analyzed results of over 18,000 vulvovaginal culture specimens obtained from sexually active 16-24-year-old females, collected between 2010 and 2018. There was significant decline in HPV infection rates in all subtypes in all age groups. Those who had been vaccinated more recently showed more reduction in HPV 6/11 than those who did not receive coverage for these strains in the earlier years of vaccination. Most notable was that the prevalence of HPV 16/18 in the 16-18-year-old cohort declined from 8.2% in 2010 to 0.0% in 2018. In the older groups, there was less decline (from 14% to 0.7% in 19-21-year-olds and 16.4% to 2.6% in 22-24-year-olds), but all reductions were statistically significant.

There was no evidence of increase in the HPV subtypes which were not included in the vaccine. Some have raised concern that vaccinating against specific HPV subtypes would increase growth of subtypes not included in the vaccine, but this was not found to be the case. While there are several limitations to this report, including the fact that each individual sample was not identified as being from a vaccinated or non-vaccinated individual, this marked reduction of all HPV subtype growth in a population which demonstrated a vaccination rate of 86% for both males and females ages 12-13 years is promising. While not all cervical cancers, throat cancers, or anal cancers are directly caused by HPV infection, the high rates of HPV-related cancers due to known HPV subtypes underscores the potential widespread benefits of this vaccine in the decades ahead.

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January, 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.

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January, 2020|Oral Cancer News|

Ask the Doctors: Dysphagia common in elderly

Source: journalstar.com
Author: askthedoctors@mednet.ucla.edu

Dear Doctor: Why do the elderly often have a hard time swallowing, and sometimes experience a feeling that food is stuck in their throats? I heard there’s a procedure to stretch the throat. Does it help?

Dear Reader: The condition you’re asking about is known as dysphagia, which refers to difficulty in swallowing. Patients may have trouble starting a swallow, or problems with the esophagus, which is the muscular tube that connects the throat with the stomach.

The origins of the disorder fall into several basic categories. There are neurological causes, such as stroke, Parkinson’s disease, multiple sclerosis, dementia and head injury. Certain muscular conditions can affect the proper functioning of the esophagus. So does obstruction, which can result from a narrowing of the esophagus, or from inflammation. These can be caused by head and neck cancers, radiation therapy, tuberculosis and chronic acid reflux.

Although dysphagia can affect people of all ages, you’re correct that it’s seen more often in older adults. This is commonly due to age-related changes in the body, such as loss of muscle tone, mass and strength, and changes to nerve function. Still, dysphagia is not considered to be a normal sign of aging.

Understanding dysphagia starts with the mechanics of swallowing. We tend to think of it as the “gulp” that empties the mouth. But that’s just the first step of a complex process.

A successful swallow moves the contents of your mouth through the throat, and all the way down to the stomach. This happens when a ring of muscles known as the upper esophageal sphincter and located at the lower end of the throat, open. Next, coordinated contractions along the length of the esophagus send the food to a second ring of muscles known as the lower esophageal sphincter. This leads to the stomach. At the same time, muscles and specialized structures within the throat prevent anything from getting into the nose, voice box and windpipe.

Symptoms of dysphagia can include pain while swallowing, struggling or being unable to swallow, feeling as though food is stuck in the esophagus, coughing or gagging when trying to swallow, regurgitation or frequent heartburn. Some people may experience drooling or develop a hoarse voice. Diagnosis of the condition includes a physical exam and any of a variety of tests that may include X-rays, muscle tests and swallowing studies.

Treatment depends on the specific cause of the condition. Patients may be asked to change their diet, use certain exercises and techniques that help with swallowing coordination or manage acid reflux with medication.

The procedure you asked about, known as esophageal dilation, is useful when dysphagia results from a narrowing of the esophagus. It involves the use of an endoscope and either plastic dilators or a special balloon to slowly and gradually stretch the esophagus. Complications, which are rare, include bleeding and tears or holes in the esophagus. In most cases, the patient is able to resume normal eating and drinking the following day.

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January, 2020|Oral Cancer News|