Cerebellar Neoplasms

The blood-brain barrierThe blood-brain barrier (BBB) is a highly selective, semipermeable endothelial boundary that restricts the nonspecific entry of solutes from circulating blood into the extracellular fluid surrounding neurons in the central nervous system. The BBB's unique regulatory properties pose challenges for the targeted delivery of therapeutics to brain parenchyma. Tight junctions between adjacent brain endothelial cells prevent paracellular transport, hindering drugs from directly accessing lesioned brain tissue. While many lipophilic drugs can enter by passive diffusion, their penetration into diseased brain tissue is often poor, necessitating high doses that can lead to substantial systemic toxicities.  Nanocarrier to cross cellular barrierMedulloblastoma patients in the Sonic hedgehog medulloblastoma subgroup (SHH-MB) face a daunting challenge as they endure poorer clinical outcomes. This is partly due to the stubborn blood-brain barrier (BBB), which impedes drug penetration into the brain at therapeutic concentrations. To make matters worse, targeted inhibition of the SHH effector Smoothened (SMO) using vismodegib can lead to severe toxicities and premature growth plate fusion. Low-dose irradiation induces P-selectin expression on tumor vasculature in medulloblastoma.A team of researchers from Memorial Sloan Kettering Cancer Center in New York decided to take on this challenge, investigating active transcellular transport mechanisms to enhance drug delivery across the BBB directly to tumor tissue.  They are certainly not alone in considering nanocarriers for help. Actually, a Synapse search indicates that major pharmaceutical companies are actively experimenting this technology. The only previous clinical trial involving nanocarriers has failed and has been withdrawn since: Good news is that another previous research has established P-selectin-targeted nanocarriers, based on the fucoidan polysaccharide for activated endothelium, which revealed that radiotherapy (RT) could increase endothelial P-selectin expression. This resulted in greater accumulation of nanocarriers at the tumor site. P-selectin aids in the transcellular transport of materials through caveolin-1 (Cav1)-mediated transcytosis across an intact BBB. In a SHH-MB genetically engineered mouse (GEM) model with an intact BBB, the researchers discovered that P-selectin targeting led to active transcytosis in tumor endothelium. This allowed fucoidan-based nanocarriers to selectively deliver cargo to the tumor microenvironment. Fucoidan nanocarriers encapsulating the inhibitor vismodegib (FiVis) exhibited potent inhibitory effects at low drug doses, with significant antitumor efficacy and the ability to reduce on-target bone toxicities. Moreover, this mechanism may also enhance drug delivery across an intact BBB to activated brain endothelium in other intracranial pathologies, offering hope for patients facing similar challenges. Targeting P-selectinThe researchers embarked on a journey to uncover the intricate workings of P-selectin expression in the SHH-MB tumor microenvironment and the effects of low-dose x-ray irradiation (XRT). Through rigorous experimentation, they discovered that whole-brain XRT increased P-selectin expression in the tumor region, while causing minimal effects in the adjacent normal cerebrum. To avoid RT-related toxicities, minimum required dose was used to enhance endothelial P-selectin expression, and a single 0.25 Gy XRT dose proved to elevate P-selectin, with significant increases observed about six hours post-XRT that persisted for at least 24 hours. P-selectin-targeted nanoparticles preferentially target SHH-MB tumours following low-dose irradiation.The nanocarriers, FiVis, were then crafted, by conjugating fucoidan polysaccharide and near-infrared dye (IRDye783), with an average diameter of 80±10 nm. The targeting and effects of radiation on FiVis delivery in SHH-MB tumors were evaluated. In unirradiated mice treated with FiVis, experiments showed slightly increased targeting to cerebellar tumors over the adjacent normal cerebrum. However, in mice pretreated with radiation (1Gy), significant FiVis accumulation was observed at the tumor site compared to wild-type (WT) mice without tumors following FiVis administration. The researchers then delved into the transcellular transport mechanisms of FiVis across the BBB. After observing increased expression of Cav1 in tumor endothelium in mice treated with FiVis,  they applied pharmacological inhibition of either caveolin- or clathrin-dependent endocytosis using methyl-β-cyclodextrin (CD; caveolar-dependent endocytosis inhibitor) or chlorpromazine (CPZ; clathrin-mediated endocytosis inhibitor) respectively, to bEnd.3 cells.  Results showed FiVis uptake significantly reduced in a dose-dependent manner after CD treatment, indicating that FiVis entry into mouse brain endothelial cells is mediated by caveolin-dependent endocytosis. Further studies were conducted to examine caveolin-mediated endocytosis using Cav1 knockout (KO) bEnd.3 cells. The results showed a significant decrease in FiVis uptake compared to WT cells. Enhancing Drug DeliveryIn order to uncover the secrets of FiVis delivery to SHH-MB tumors, the researhcers propagated SHH-MB tumors lacking Cav1 in mice. After low-dose XRT, FiVis nanocarrier accumulation reduced in the tumor region of these Cav1KO SHH-MB mice, despite their presence within the tumor vasculature. These findings illuminated the intricate mechanisms of FiVis delivery to SHH-MB tumors and offered hope for overcoming the daunting challenge posed by the BBB. Passage of FiVis nanoparticles across the BBB is mediated by Cav1.The therapeutic efficacy of FiVis in the SHH-MB GEM model was then assessed. Mice with established tumors were treated with FiVis or free vismodegib at an equivalent dose. The results were astounding - FiVis treatment significantly inhibited tumor growth compared to free vismodegib. Importantly, FiVis treatment was associated with an absence of premature growth plate fusion, a common adverse effect of vismodegib therapy, indicating reduced bone toxicity. Pre-treatment with XRT further enhanced FiVis delivery and therapeutic efficacy, with significant inhibition of tumor growth even at a lower drug dose. Survival analysis revealed that mice treated with FiVis at a lower dose survived significantly longer than those treated with free vismodegib. To gain a better understanding of the mechanism of FiVis delivery, in vivo imaging was conducted. Fluorescence microscopy of brain sections from mice treated with FiVis revealed a greater accumulation of the nanocarrier in the tumor region compared to the adjacent normal cerebrum. This confirmed the preferential delivery of FiVis to the tumor site. Fucoidan-based nanocarriers can actively transport therapeutic cargo across tumor endothelium, allowing for targeted delivery to the tumor microenvironment. This approach holds immense potential to revolutionize therapeutic outcomes for diseases with an intact BBB, such as SHH-MB, and could usher in a new era of improved therapies for a multitude of brain diseases. Reference Tylawsky, D.E., Kiguchi, H., Vaynshteyn, J. et al. P-selectin-targeted nanocarriers induce active crossing of the blood–brain barrier via caveolin-1-dependent transcytosis. Nature Materials 22, 391–399 (2023).

Care is increasingly shifting from the hospital to the home, driven by factors such as a growing elderly population, the proliferation of virtual care options during the pandemic and reduced expenses for payers. Investors seem to have recognized this movement —at-home care was one of the three main categories within digital health that received the most venture investment during the first half of the year, along with value-based care and technology to improve healthcare’s workforce management. The home healthcare market was valued at $281.8 billion in 2020, but Grand View Research predicted last month that the market will reach $666.9 billion by 2030. Additionally, the White House’s budget includes $150 billion to improve and expand Medicaid home care services over the next decade. Yet, there are several misconceptions about this market, including the misbelief that at-home care is only for senior citizens and that this care model lacks scalability. The pandemic was the “initial forcing function” that necessitated the shift from hospital-based care to home-based care, said Yoni Shtein, CEO of Laguna Health, in a recent interview. His startup offers an AI-powered contextual care management platform that scales personalized care for patients as they transition from hospital care to at-home care. It raised $15 million in Series A financing in May. “During Covid, health systems expanded telehealth services out of necessity and, more importantly, expanded provider reimbursement to include parity for virtual care while also expanding coverage to include remote patient monitoring,” Shtein declared. While the healthcare industry is getting more and more comfortable with the idea that care needs to be expanded beyond the four walls of a hospital, he pointed out that some industry stakeholders still think that the physical provision of home care is too expensive and difficult to scale. In reality, some patients need in-home skilled nursing in which they are physically tended to, but many can manage their health via lower-cost options like telehealth appointments and wearable remote monitoring devices, Shtein explained. Another common misconception is the belief that home-based care is primarily for elderly individuals, said Vijay Kedar, CEO of Tomorrow Health. His company — which seeks to make it easier for patients, providers and payers to coordinate home-based — has raised $92.5 million since being founded in 2018. While older adults do represent a significant portion of the population receiving at-home care, this type of care can be provided to all age groups, Kedar declared. “For example, at Tomorrow Health, patients range from a 23-year-old female with congenital muscular dystrophy to a 15-year-old quadriplegic with chronic feeding difficulties as well as a 12-year-old male with a cerebellar tumor — with needs for everything from a hospital bed to nutrition supplies to continuous glucose monitors,” he said. Kedar also pushed back against the idea that care provided at home is lower in quality than care provided in a hospital or nursing home, arguing that well-managed home healthcare programs can provide comparable or even better outcomes in terms of patient satisfaction, health improvement and cost-effectiveness. He also pointed out that at-home care allows patients to receive personalized care in the comfort of their own homes, which can contribute to better overall wellbeing. Researchers will likely produce more data backing up the arguments made by Kedar and Shtein as the healthcare industry continues to embrace more home healthcare models. The first half of 2023 has already seen some megadeals in the at-home care space, including Monogram Health‘s $375 million fundraise and Author Health‘s $115 million financing round.

The grants were awarded through the FDA’s Orphan Products Clinical Trials Grants Program that was provided by Congress to specifically encourage the development of treatments for rare diseases. The U.S. Food and Drug Administration (FDA) awarded $15 million in grants to fund 12 new clinical trials over the next four years to foster the development of rare disease treatments. The grants were awarded through the FDA’s Orphan Products Clinical Trials Grants Program that was provided by Congress to specifically encourage the development of treatments for rare diseases. The grants are intended to substantially contribute to the marketing approval of products to treat rare diseases or provide essential data needed for the development of such products. The FDA selected the 12 recipients out of 89 different applications that were evaluated by more than 100 rare disease experts, the agency said. FDA Principal Deputy Commissioner Amy Abernethy said the regulatory agency has provided “much-needed financial support” to clinical trials for rare disease treatments for more than three decades. Over that time, the more than $400 million provided by these grants has led to the approval of more than 60 different drugs for rare diseases, she said. “We are encouraged by the amount of interest we continue to have in the grants program and are committed to working with researchers and industry to facilitate and support the study and development of treatments for patients with rare diseases,” Abernathy said in a statement. The 12 grant awards are primarily focused on discovering treatments for rare diseases affecting children, with about two-thirds looking at rare cancers, including a type of brain cancer. More than three-fourths of the trials will enroll children, including infants, the FDA said. Some of these diseases include Duchenne Muscular Dystrophy, sickle cell disease and Fanconi Anemia, a rare inherited condition that can result in bone marrow failure and has a high risk for squamous cell cancers. Another of the funded studies is evaluating a novel drug delivery system that delivers chemotherapy on a sustained basis directly to the eye to treat retinoblastoma, a rare cancer in the eye most commonly affecting young children. Janet Maynard, director of the FDA’s Office of Orphan Products Development, said the majority of rare diseases do not have approved therapies and this grant program is aimed at the hope of developing treatments for these diseases. “By helping to spark research, we hope to speed the development of products for rare diseases, and ultimately, make needed treatments available to those patients who need them most,” Maynard said. The awarded grants are: Chemocentryx, Inc. -- $1 million over two years to support a Phase II study of avacopan for the treatment of complement 3 glomerulopathy Cincinnati Children’s Hospital Medical Center -- $750,000 over three years to support a Phase I study of PTC596 for the treatment of diffuse intrinsic pontine glioma & high-grade gliomas Cincinnati Children’s Hospital Medical Center -- $1.7 million over four years to fund a Phase II study of quercetin chemoprevention for the treatment of squamous cell carcinoma in patients with Fanconi Anemia Columbia University Health Sciences -- $2 million over four years for a Phase II study of daily vitamin D for the treatment of sickle-cell respiratory complications Cumberland Pharmaceuticals, Inc. -- $1 million over three years to support a Phase II study for oral ifetroban for the treatment of cardiomyopathy associated with Duchenne muscular dystrophy Massachusetts General Hospital -- $1 million over three years to fund a Phase II study of anti-PD1 therapy for the treatment of HPV-associated recurrent respiratory papillomatosis New York Medical College -- $1.7 million over four years to support a Phase II study of viral-specific cytotoxic T-lymphocytes for the treatment of refractory viral infections and T-cell immunodeficiency Privo Technologies, LLC. -- $2 million over four years to fund a Phase I/II study of cisplatin patch (PRV111) for the treatment of oral cancer Targeted Therapy Technologies, LLC -- A Phase 1 study of episcleral topotecan for the treatment of retinoblastoma will receive $660,000 in support over three years University of Alabama at Birmingham -- $750,000 over three years to support a Phase I study of oncolytic engineered herpes simplex virus therapy for the treatment of pediatric malignant cerebellar brain tumors University of California San Diego – A Phase II study of temozolomide for the treatment of gastrointestinal stromal tumor will received $1.5 million over three years University of Texas MD Anderson Cancer Center – A Phase I/II study of imipridone for treatment of acute myeloid leukemia will receive $1 million over four years. hbspt.forms.create({ portalId: "4413123", formId: "a126e976-bca0-4c13-aa9b-02e8feb92096" });