glioblastomas Archives - Amazing Health Advances

A Potential New Treatment for Brain Tumors

AHA Publisher — Wed, 28 Sep 2022 07:00:11 +0000

University of Cincinnati via Newswise – A research question posed in Pankaj Desai’s lab has led to a decade of research, a clinical trial and major national funding to further investigate a potential new treatment for the most deadly form of brain tumors. Desai, PhD, and his team at the University of Cincinnati recently received a $1.19 million grant from the National Institutes of Health/National Institute of Neurological Disorders and Stroke to continue research into the use of a drug called letrozole to treat glioblastomas (GBM). Research Progression GBMs are aggressive brain tumors that patients often are unaware of until symptoms emerge and the tumor is substantial. Current treatments include immediate surgery to safely remove as much tumor as possible, radiation and chemotherapy, but the tumor often recurs or becomes resistant to treatments. The average patient survives no more than 15 months after diagnosis. The medication letrozole was approved by the U.S. Food and Drug Administration as a treatment for postmenopausal women with breast cancer in 2001. The drug works by targeting an enzyme called aromatase that is present in breast cancer cells and helps the cancer grow. In the fall of 2012, Desai and a doctoral student in his lab, Nimita Dave (now a senior pharmacologist at a biotech company in Boston), asked a question: Does aromatase play a similar role in GBM tumors, and if so, will letrozole work as an effective treatment? Early research in the lab found the enzyme was present in brain tumor cell lines, and further testing found a very high amount of aromatase at protein and mRNA levels in brain tumor samples from UC’s tumor bank. However, that did not guarantee that letrozole would be similarly effective in brain tumors like it is in breast cancer tumors. Desai explained a defense system called the blood-brain barrier only allows certain compounds into the brain based on their physical and chemical properties. “Otherwise any compound could come into the brain and cause havoc and neurotoxicity,” said Desai, professor and chair of the Pharmaceutical Sciences Division in UC’s James L. Winkle College of Pharmacy and a University of Cincinnati Cancer Center member. “There are other compounds similar to letrozole, but we went with letrozole because we figured that based on its properties, this compound actually has the best chance of getting through into the brain from the blood circulation.” Studies in animal models showed that letrozole was effective, and Desai’s research group moved to test the compound in cells derived from human brain tumor tissues. In this phase of work, key contributions were made by current doctoral student Aniruddha Karve who will continue to work with Desai as a postdoctoral fellow on the new NIH grant. “What we saw in the patient-derived cells is that letrozole is very effective in killing the tumor cells in cell culture models,” Desai said. With funding support from the Cancer Center and the UC Brain Tumor Center, Desai’s team launched a phase 0/1 clinical trial testing what dosage of letrozole is appropriate to treat glioblastomas. This trial was led by Trisha Wise-Draper, MD, PhD, an expert in phase 1 oncology trials with contributions from several other neuro-oncologists and neurosurgeons. The trial is set to be completed soon, but Desai said early results have shown the drug is “unequivocally” reaching its target of the brain tumor tissue safely. Preliminary results also show that doses of letrozole higher than those needed for breast cancer treatment can be safely achieved in GBM patients. New Research While the body of research results has been encouraging so far, Desai said GBMs remain a complicated, aggressive form of brain cancer. As promising as letrozole is, it is still unlikely that the drug will be a singular cure for the disease. “We hope that would work, but it’s not necessarily rooted in reality. It’s going to be a combination of drugs,” Desai said. Supported by the new NIH/NINDS funding, Desai and his team will research the preclinical effectiveness of combining letrozole with other chemotherapy compounds. The three-year grant began Aug. 1. “It’s really exciting to get this sort of reassurance from a peer reviewed grant application,” Desai said. “And it’s an exciting time. I think finding a cure for a disease like GBM is like finding a needle in a haystack, and we hope that it’s going to really work, and that’s what we are all striving for.” Desai said the research has been and continues to be a collaborative effort between UC colleagues from the College of Pharmacy, Cancer Center and Brain Tumor Center. “It’s really a beautiful collaboration, and I’m most grateful for that,” Desai said. “This is a disease where an urgent breakthrough is absolutely needed, and our team along with others in the field are really striving to make a difference.” David Plas, PhD, professor and Anna and Harold W. Huffman endowed chair in glioblastoma experimental therapeutics in the Department of Cancer Biology in UC’s College of Medicine and a Cancer Center member, and his research group are joining the team as the new project launches. Plas said his lab has focused on tumors deficient in a tumor-suppressing protein called PTEN, and the new research may reveal how letrozole in combination with other therapies may lead to a suitable treatment for PTEN-deficient glioblastomas. “This new collaboration will combine my group’s experience in glioblastoma experimental therapeutics with Dr. Desai’s experience in GBM therapeutics and pharmacokinetics,” Plas said. “By investigating possible combinations with letrozole for GBM therapy, this new project has the potential for faster translation to clinical trial. It is exciting to work with Desai on this new project.” To read the original article click here.

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Targeted Drug Combination Shows Unprecedented Activity in Some Highly Aggressive Brain Tumors

AHA Publisher — Wed, 01 Dec 2021 08:00:09 +0000

Dana-Farber Cancer Institute via Newswise – A combination of two targeted cancer drugs showed unprecedented, “clinically meaningful” activity in patients with highly malignant brain tumors that carried a rare genetic mutation, according to a clinical trial report by investigators from Dana-Farber Cancer Institute. The drug combination, which blocked an overactive cell-growth signaling pathway, shrank tumors by 50% or more in one-third of 45 patients with hard-to-treat high-grade gliomas, including glioblastomas, the most aggressive brain tumor. The patients were selected for the trial because their tumors carried a genetic mutation known as v600E in the BRAF gene. This mutation is found in only two to three percent of patients with high-grade gliomas but is found in up to 60% of certain types of low-grade gliomas. The study included 13 patients with low-grade gliomas. Of those patients, nine had an objective response to treatment with the drug combination, for a response rate of 69%. “This is the first time that any targeted drug has been shown to work in glioblastoma in a clinical trial,” said Patrick Wen, MD, first author of the report in The Lancet Oncology and director of the Center for Neuro-Oncology at Dana-Farber. With all current chemotherapy treatments for glioblastomas, the response rate is no better than five per cent, he said, which contrasts with the 33 percent response rate achieved by the combination. The response rate was even higher – about 40 % – in patients younger than 40 years of age, according to Wen. The two drugs paired in the study were dabrafenib and trametinib. Both drugs target proteins in the MAPK pathway, a signaling chain of proteins that acts as a switch for cell growth and can become stuck in the “on” position, causing uncontrolled growth leading to tumors. Three patients had complete responses – their tumors no longer could be seen on imaging scan – and 12 had partial shrinkage of their tumors. The patients were not cured, but those who responded to the drugs experienced remarkably durable benefits – by one assessment, the median duration of response was 13.6 months, and by another assessment, it was 36.9 months. The findings are from an ongoing phase 2 study called ROAR (Rare Oncology Agnostic Research) that has been enrolling patients since 2014 in 27 community and academic cancer centers in 13 countries. The study is a so-called “basket” trial, which seeks to enroll patients who share a common tumor characteristic – in this case the BRAF v600E mutation – although they may have an array of different cancers. The ROAR study includes patients with thyroid and biliary tract cancers, gastrointestinal stromal tumors, hairy cell leukemia, multiple myeloma, low- and high-grade glioma brain tumors, and others. The study is designed to determine the overall response rate of dabrafenib combined with trametinib in patients with BRAF V600E-mutated cancers. The BRAF protein is a growth signaling protein kinase that plays a role in regulating the MAPK signaling pathway. BRAF V600E mutations drive cancer by activating the MAPK pathway, which is made up of many proteins, resulting in uncontrolled cell growth and the development of a tumor. The drugs used in this study, dabrafenib and trametinib, are oral drugs that block parts of the overactive MAPK signaling pathway. Dabrafenib inhibits an enzyme, B-Raf, and trametinib inhibits molecules called MEK1 and MEK2, which are part of the MAPK pathway. They have been used in combination to treat melanoma, non-small cell lung cancer, and thyroid cancer. Gliomas are cancer that originate in the glia – the supporting cells of the brain – not the brain neurons themselves. Gliomas comprise about 80 percent of all malignant brain tumors. Some are slow-growing low-grade gliomas, while others are aggressive high-grade gliomas including glioblastomas that are difficult to remove and almost always recur. No important advances in treating gliomas in recent years, the authors of the report said, but there have been isolated reports of the combination of dabrafenib and trametinib showing activity in gliomas. Their report from the ROAR study “is the first time that a combination of BRAF inhibitor (dabrafenib) and a MEK inhibitor (trametinib) have shown notable activity in these difficult-to-treat gliomas, including glioblastomas which have historically shown resistance to therapies.” Although the drugs only helped patients whose tumors carried the rare V600E mutation, Wen said the results were encouraging “because people were starting to think you will never have any targeted therapies for glioblastoma.” He added that there is emerging evidence that there may be other targets in gliomas that could be blocked by designer drugs. To read the original article click here.

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