{"id":27957,"date":"2022-02-25T12:00:00","date_gmt":"2022-02-25T12:00:00","guid":{"rendered":"https:\/\/www.cancer.gov\/news-events\/cancer-currents-blog\/2022\/medulloblastoma-nanoparticle-palbociclib-sapanisertib"},"modified":"2024-11-03T15:13:43","modified_gmt":"2024-11-03T15:13:43","slug":"experimental-medulloblastoma-treatment-gets-a-boost-with-nanoparticles","status":"publish","type":"post","link":"https:\/\/ogkologos.com\/en\/experimental-medulloblastoma-treatment-gets-a-boost-with-nanoparticles\/","title":{"rendered":"Experimental Medulloblastoma Treatment Gets a Boost with Nanoparticles"},"content":{"rendered":"

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The nanoparticle is made of a flexible polymer (blue) that assembles into tiny soap bubble\u2012like shapes with the drug (red) cradled in the center.<\/p>\n

Credit: Marina Sokolsky-Papkov, UNC-Chapel Hill<\/p>\n<\/p><\/div>\n<\/figcaption><\/figure>\n<\/p><\/div>\n

A new study in mice has shown that loading the cancer drug palbociclib (Ibrance)<\/a> in nanoparticles<\/a> can boost its ability to fight medulloblastoma<\/a>, a type of brain cancer. The nanoparticle coating helps the drug reach tumors better and stay in the body longer, according to the researchers who led the study.<\/p>\n

Medulloblastoma<\/a> is a rare, aggressive brain cancer that affects children and young adults. While most patients are cured with surgery, radiation, and chemotherapy, they are typically left with debilitating side effects. And for the 1 in 5 people whose cancer comes back after initial therapy, there are no highly effective treatment options.<\/p>\n

So, \u201calthough standard medulloblastoma therapy is effective for most patients, it\u2019s still not really satisfactory, with disabling toxicity<\/a> and too many failures,\u201d said pediatric neuro-oncologist, Timothy Gershon, M.D., Ph.D., of the University of North Carolina (UNC) Lineberger Comprehensive Cancer Center in Chapel Hill, one of the study\u2019s lead researchers.<\/p>\n

The study showed that palbociclib on its own didn\u2019t shrink medulloblastoma tumors in mice, and the mice died quickly. When the researchers treated mice with palbociclib loaded in nanoparticles, the mice lived longer but their tumors eventually grew back<\/a>.<\/p>\n

However, mice treated with nanoparticles containing both palbociclib and another drug, sapanisertib<\/a>, lived substantially longer than those treated with either drug alone. Results of the study, partially funded by NCI, were published January 26 in Science Advances<\/em>.<\/p>\n

\u201cOne of the challenges of treating medulloblastoma is drug penetration into tumors, and it does seem like this nanoparticle formulation makes the drug better at precisely that: entering the brain and getting into tumors,\u201d said Marta Penas-Prado, M.D., of NCI\u2019s Center for Cancer Research<\/a>. Dr. Penas-Prado, who cares for adult patients with medulloblastoma, was not involved in the study.<\/p>\n

Given these promising results from the mouse study, \u201cwe are brainstorming ways to bring this approach to clinical trials,\u201d said the study\u2019s other lead researcher, Marina Sokolsky-Papkov, Ph.D., of UNC-Chapel Hill.<\/p>\n

Shortcomings of palbociclib<\/h2>\n

Palbociclib is a targeted therapy<\/a> that blocks a pair of proteins\u2014CDK4 and CDK6\u2014that act abnormally in some tumors, driving them to grow out of control. It is currently used as a breast cancer treatment and is being studied as a treatment for other cancers with abnormal CDK4 and CDK6 activity, including medulloblastoma.<\/p>\n

For their study, the researchers used mice that were genetically engineered<\/a> to develop medulloblastoma tumors a few days after birth. Without any treatment, these mice survived just a few days after developing tumors.<\/p>\n

Treating the mice with palbociclib didn\u2019t help the mice live any longer, the researchers found. That\u2019s because the drug doesn\u2019t get into the brain easily, explained Dr. Sokolsky-Papkov.<\/p>\n

In such cases, she said, \u201cthe traditional approach is, \u2018let\u2019s try a higher dose to get a bit more into the brain.\u2019 But everything that\u2019s not getting into the brain is ending up somewhere else in the body and creating toxicity.\u201d<\/p>\n

Instead, the team designed a nanoparticle that they hoped would help palbociclib reach tumors in the brain and make it less toxic to the rest of the body. To create the nanoparticle, they used a flexible polymer that assembles into tiny soap bubble\u2012like shapes called micelles<\/a> that cradle the drug in the center. Once inside the body, the nanoparticles slowly release the encapsulated drugs.<\/p>\n

\u201cOur polymer is unique in the way that it can hold a lot of the drug inside,\u201d said Dr. Sokolsky-Papkov, whose research focuses on nanotechnology-based drug delivery systems. \u201cAlso, it has the capability to hold several drugs in the same micelle.\u201d<\/p>\n

Nanoparticles help palbociclib reach brain tumors<\/h2>\n

The team\u2019s nanoparticle appeared to hit the nail on the head: the peak concentration of the palbociclib\u2012nanoparticle in mouse tumors was 75% higher than that of regular palbociclib. The nanoparticle form also stayed in the bloodstream longer.<\/p>\n

Compared with regular palbociclib, the same dose of the palbociclib\u2012nanoparticle was less toxic to the mice. The highest dose of the palbociclib\u2012nanoparticle that the mice were able to tolerate was 5 times that of regular palbociclib, the scientists found.<\/p>\n

That\u2019s likely because the nanoparticle coating prevents palbociclib from \u201charming the abdominal organs. [The drug is] in the nanoparticle and not interacting with parts of the body we don\u2019t want it to,\u201d like the kidneys and liver, Dr. Gershon explained.<\/p>\n

The palbociclib\u2012nanoparticle was also effective against the cancer. The nanoparticle slowed the growth of medulloblastoma tumors, and mice treated with the nanoparticle lived longer than those treated with regular palbociclib (median survival<\/a> of 22 days versus 17 days).<\/p>\n

Combination treatment sidesteps drug resistance<\/h2>\n

Although the palbociclib\u2012nanoparticle shrank medulloblastoma tumors in mice, the effects didn\u2019t last long, and the tumors began to grow again after a few days.<\/p>\n

Scientists call this phenomenon drug resistance<\/a>: When cancer cells grow readily despite the presence of a drug that once killed them.<\/p>\n

Drug resistance \u201cis a challenge that happens very often in the treatment of tumors,\u201d Dr. Penas-Prado said. \u201cIf you target one specific pathway, [tumors] have ways to compensate for that by using other pathways to keep growing.\u201d<\/p>\n

By looking at individual cancer cells, the research team found that cells that were resistant to palbociclib\u2012nanoparticles had reduced activity of a protein called mTOR<\/a>. The scientists reasoned that while lower mTOR activity might help cancer cells resist palbociclib treatment, they may be unable to survive if mTOR activity is wiped out entirely.<\/p>\n

So, the team loaded nanoparticles with both palbociclib and sapanisertib, an investigational drug that blocks mTOR, to see if further reducing the activity of this protein would shrink tumors for longer.<\/p>\n

Mice treated with the two-drug nanoparticles lived substantially longer than those treated with nanoparticles containing either drug alone. All of the mice treated with palbociclib\u2012nanoparticles or sapanisertib\u2012nanoparticles died within 30 days, but 70% of the mice treated with the two-drug nanoparticles lived for more than 35 days.<\/p>\n

These mice have a very aggressive form of medulloblastoma, Dr. Sokolsky-Papkov said, so \u201cseeing a response like this, where the mice are living so much longer\u2014this result is amazing.\u201d<\/p>\n

Looking toward clinical trials<\/h2>\n

While the results are promising, this approach has only been tested in mice so far, Dr. Penas-Prado cautioned. \u201cWhether the toxicity profile, safety, and efficacy [of the nanoparticle] are similar, better, or worse in humans remains to be proven,\u201d she said.<\/p>\n

Before moving to studies in people, the team needs to do more lab studies on the safety of their nanoparticle, Dr. Sokolsky-Papkov explained. The polymer in the nanoparticle has not been approved for use in humans, so they can\u2019t move ahead to clinical studies just yet, she said.<\/p>\n

But looking ahead, Dr. Gershon said they hope to test the palbociclib\u2012nanoparticle in a clinical trial \u201cspecifically for people with recurrent<\/a> medulloblastoma because they don\u2019t have good [treatment] options.\u201d<\/p>\n

Dr. Penas-Prado agreed, adding that eventually it \u201ccould also be tested as an adjuvant<\/a> to up-front therapy with the intention of decreasing the dose of radiation<\/a> that [patients] need to receive.\u201d That could potentially lessen the amount of damage radiation does to developing bodies, she said.<\/p>\n

Even beyond that, this nanoparticle approach has the potential to improve treatments for other kinds of brain cancer, Dr. Gershon noted. The team plans to study the approach in a mouse model<\/a> of glioblastoma, he added.<\/p>\n

Source<\/a><\/p>\n","protected":false},"excerpt":{"rendered":"

February 25, 2022, by NCI Staff The nanoparticle is made of a flexible polymer (blue) that assembles into tiny soap bubble\u2012like shapes with the drug (red) cradled in the center. Credit: Marina Sokolsky-Papkov, UNC-Chapel Hill A new study in mice has shown that loading the cancer drug palbociclib (Ibrance) in nanoparticles can boost its ability […]<\/p>\n","protected":false},"author":2,"featured_media":27958,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_monsterinsights_skip_tracking":false,"footnotes":""},"categories":[5137],"tags":[],"class_list":["post-27957","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-world-news"],"_links":{"self":[{"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/posts\/27957","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/comments?post=27957"}],"version-history":[{"count":1,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/posts\/27957\/revisions"}],"predecessor-version":[{"id":44982,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/posts\/27957\/revisions\/44982"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/media\/27958"}],"wp:attachment":[{"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/media?parent=27957"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/categories?post=27957"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/tags?post=27957"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}