Source: www.eurekalert.org
\nAuthor: Boston University<\/p>\n
The most common head and neck cancer\u2014oral squamous cell carcinoma\u2014often starts off, as many other cancers do, quite innocently. Perhaps as a little white patch in the mouth or a small red bump on the gums. Easy to ignore, to downplay. But then something changes, and the little blotch becomes more ominous, starts growing, burrowing into connective tissue.<\/p>\n
Patients who are lucky enough to see a dentist before things take a nasty turn have a shot at being able to prevent the lesions from turning cancerous\u2014or can at least make sure treatment starts when it\u2019s most effective. But for those who aren\u2019t that lucky, the outlook can be bleak: the five-year survival rate of oral squamous cell carcinoma (OSCC) is around 66 percent. More than 10,000 Americans die of oral cancer every year; smokers and drinkers are hardest hit.<\/p>\n
Now, researchers at Boston University\u2019s Henry M. Goldman School of Dental Medicine have found that dialing back\u2014or even genetically deleting\u2014a protein that seems to spur the cancer\u2019s growth might help limit a tumor\u2019s development and spread. They say their findings make the protein, an enzyme called lysine-specific demethylase 1, a potential \u201cdruggable target\u201d\u2014something that doctors could aim chemo and immuno-oncology therapies at to take down a tumor. The study was published in February in Molecular Cancer Research<\/em>.<\/p>\n Given that at least one-third of Americans don\u2019t visit a dentist regularly, according to the Centers for Disease Control and Prevention, the discovery could be a future lifesaver for those who miss out on preventative care.<\/p>\n \u201cThese findings have significant implications for new and potentially more effective therapies for oral cancer patients,\u201d says Manish V. Bais, a lead author on the study and SDM assistant professor of translational dental medicine. \u201cThis study is an important step toward the development of novel groundbreaking therapies to treat oral cancer.\u201d<\/p>\n Maria Kukuruzinska, SDM\u2019s associate dean for research and a coauthor on the study, says it was rare in the past for dental schools to be diving into the science behind head and neck cancers, with most of the research happening in cancer centers. But that\u2019s changing and \u201cdental schools have an advantage over traditional cancer centers when it comes to investigating the science behind the development of OSCC,\u201d she says, \u201cbecause we can get access to premalignant lesions, where cancer centers basically just see patients who are presenting with fully developed disease.\u201d<\/p>\n Helping the Body Fight Back: Anti-Tumor Immunity<\/u> In previous research, Bais had found that lysine-specific demethylase 1 (LSD1)\u2014an enzyme that typically plays a crucial role in normal cell and embryo development\u2014goes out of control, or is \u201cinappropriately upregulated,\u201d in a range of cancers, including in the head and neck, as well as those in the brain, esophagus, liver, and lung.<\/p>\n \u201cThe expression of this enzyme goes up with each tumor stage,\u201d says Bais, who\u2019s also a member of BU\u2019s Center for Multiscale & Translational Mechanobiology. \u201cThe worse the tumor, the higher the expression of this protein.\u201d<\/p>\n In his lab, Bais began testing what would happen to tumors in the tongue if LSD1 was blocked. To restrict the enzyme, the researchers either knocked it out\u2014by manipulating genes so LSD1 is effectively switched off\u2014or used a type of drug called a small molecule inhibitor, which enters a cell and impedes its normal function. Already in clinical trials for treating other cancers, small molecule inhibitors haven\u2019t previously been tested against oral cancer. Bais found that disrupting LSD1 curbed the tumor\u2019s growth.<\/p>\n \u201cThe aggressiveness, or bad behavior, of the tumor went down,\u201d he says. \u201cWe found that when we inhibit this protein, it promotes anti-tumor immunity\u2014our body tries to fight by itself.\u201d<\/p>\n But LSD1 isn\u2019t the only troublemaker in the tumor: when it\u2019s upregulated, it messes with a cell communication process\u2014the Hippo signaling pathway-YAP\u2014that normally helps control organ growth and tissue regeneration. Bais says YAP, LSD1, and a couple of other proteins then get stuck in a vicious cycle, each one pushing the other into increasingly aggressive and harmful moves. \u201cWe need to break this cycle,\u201d says Bais.<\/p>\n To find a new way of doing that, the researchers coupled the effort to inhibit LSD1 by targeting YAP with a different inhibitor, a drug called verteporfin. Originally developed to help treat serious eye conditions like macular degeneration, verteporfin is being tested by other researchers as a potential cancer treatment, including in ovarian cancer. The combination proved effective, according to Bais. He also threw a third drug into the mix. Bais says using the LSD1 inhibitor in combination with a common immunotherapy drug that helps white blood cells in the immune system kill cancer cells\u2014an immune checkpoint inhibitor called anti-Programmed Death 1 ligand antibody\u2014\u201cshowed a favorable response.\u201d<\/p>\n \u201cOur findings provide a basis for future clinical studies based on the inhibition of LSD1, either as monotherapy or in combination with other agents to treat oral cancer in humans,\u201d he says. The work was recently boosted with a new $2.6 million National Institute of Dental and Craniofacial Research grant. \u201cAlthough our studies are preclinical, restricted to mice and some human tissue, we want to expand to look at human clinical trial samples.\u201d<\/p>\n Predict Success in Humans<\/u> \u201cPeople get very excited when you have a drug that may show some positive preliminary results, but very frequently, these studies move forward to humans, cost billions of dollars, and then eventually fail,\u201d says Kukuruzinska, who\u2019s also director of SDM\u2019s predoctoral research program and a professor of translational dental medicine. \u201cIf you really understand what pathways, what cell processes are impacted by these inhibitors, then it allows you to predict in advance whether something is going to be successful in human patients.\u201d<\/p>\n At BU, the dental school has a teaching clinic on site and shares a campus with the BU School of Medicine and its primary teaching hospital, Boston Medical Center. It\u2019s also home to BU\u2019s Head & Neck Cancer Program\u2014which pairs basic science researchers with clinicians to look at the underlying mechanisms of oral cancers\u2014and Center for Oral Diseases, a multidisciplinary clinical-research collaborative.<\/p>\n \u201cSo, we can think about disease interception,\u201d says Kukuruzinska. \u201cAnd perhaps think about preventing the tumor from happening.\u201d<\/p>\n With access to a clinic\u2014as well as head and neck surgeons from the neighboring hospital\u2014researchers like Bais can test any new treatments and approaches on human tissue samples.<\/p>\n \u201cIt\u2019s a holy grail,\u201d Kukuruzinska says of the human samples. \u201cWe can interrogate them for responses to small molecule inhibitors, by capturing tumor slices and trying to treat them with different inhibitors to see the response.\u201d<\/p>\n Eventually, it could also open the door to personalized, precision medicine, with researchers trialing different therapies on tissue from individual patients. \u201cAnd then it will predict whether this person can be treated with this study,\u201d says Kukuruzinska. \u201cThis is something we really want to develop.\u201d<\/p>\n With students involved in many of the research projects\u2014three were coauthors on Bais\u2019 paper and another, Thabet Alhousami (SDM\u201922), was a lead author\u2014it means future dentists produced at BU will head into the clinic with a sharper eye for potential malicious bumps and blotches.<\/p>\n \u201cThey will be able to say, \u2018This is precancerous or cancerous\u2019\u2014it will impact their diagnoses,\u201d says Bais. \u201cThen, in terms of therapy, because they\u2019re now aware of what can work, what immunotherapy can work, they can make specific reference to where patients should go next. It can improve the quality of diagnosis and treatment in the long term.\u201d<\/p>\n Journal Source: Source: www.eurekalert.org Author: Boston University The most common head and neck cancer\u2014oral squamous cell carcinoma\u2014often starts off, as many other cancers do, quite innocently. Perhaps as a little white patch in the mouth or a small red bump on the gums. Easy to ignore, to downplay. But then something changes, and the little blotch becomes more ominous, starts growing, burrowing into connective tissue. Patients who are lucky enough to see a dentist before things take a nasty turn have a shot at being able to prevent the lesions from turning cancerous\u2014or can at least make sure treatment starts when it\u2019s most effective. But for those who aren\u2019t that lucky, the outlook can be bleak: the five-year survival rate of oral squamous cell carcinoma (OSCC) is around 66 percent. More than 10,000 Americans die of oral cancer every year; smokers and drinkers are hardest hit. Now, researchers at Boston University\u2019s Henry M. Goldman School of Dental Medicine have found that dialing back\u2014or even genetically deleting\u2014a protein that seems to spur the cancer\u2019s growth might help limit a tumor\u2019s development and spread. They say their findings make the protein, an enzyme called lysine-specific demethylase 1, a potential \u201cdruggable target\u201d\u2014something that doctors could aim chemo and immuno-oncology therapies at to take down a tumor. The study was published in February in Molecular Cancer Research. Given that at least one-third of Americans don\u2019t visit a dentist regularly, according to the Centers for Disease Control and Prevention, the discovery could be a future lifesaver for […]<\/p>\n","protected":false},"author":2,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[1],"tags":[361,6230,439,6231,6232],"class_list":["post-21236","post","type-post","status-publish","format-standard","hentry","category-oral_cancer_news","tag-lesions","tag-lysine-specific-demethylase-1","tag-protein","tag-upregulated","tag-verteporfin"],"_links":{"self":[{"href":"https:\/\/oralcancernews.org\/wp\/wp-json\/wp\/v2\/posts\/21236","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/oralcancernews.org\/wp\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/oralcancernews.org\/wp\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/oralcancernews.org\/wp\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/oralcancernews.org\/wp\/wp-json\/wp\/v2\/comments?post=21236"}],"version-history":[{"count":4,"href":"https:\/\/oralcancernews.org\/wp\/wp-json\/wp\/v2\/posts\/21236\/revisions"}],"predecessor-version":[{"id":21240,"href":"https:\/\/oralcancernews.org\/wp\/wp-json\/wp\/v2\/posts\/21236\/revisions\/21240"}],"wp:attachment":[{"href":"https:\/\/oralcancernews.org\/wp\/wp-json\/wp\/v2\/media?parent=21236"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/oralcancernews.org\/wp\/wp-json\/wp\/v2\/categories?post=21236"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/oralcancernews.org\/wp\/wp-json\/wp\/v2\/tags?post=21236"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}
\nOnce OSCC takes hold, says Bais, there\u2019s little chance of eliminating it completely. Clinicians can try chemotherapy and radiotherapy, even cutting out a tumor. \u201cBut there is no cure\u2014you can shrink the tumor, but not eliminate it,\u201d Bais says.<\/p>\n
\nAccording to Kukuruzinska, Bais\u2019 focus on the biology of oral cancer may also help make the development of other future treatments more efficient.<\/p>\n
\n“Inhibition of LSD1 attenuates oral cancer development and promotes therapeutic efficacy of immune checkpoint blockade and YAP\/TAZ inhibition”, Molecular Cancer Research<\/em>, 1-Feb-2022<\/p>\n","protected":false},"excerpt":{"rendered":"