NEO212, temozolomide conjugated to NEO100, exerts superior therapeutic activity over temozolomide in preclinical chemoradiation models of glioblastoma.

Background: The chemotherapeutic standard of care for patients with glioblastoma (GB) is radiation therapy (RT) combined with temozolomide (TMZ). However, during the twenty years since its introduction, this so-called Stupp protocol has revealed major drawbacks, because nearly half of all GBs harbor intrinsic treatment resistance mechanisms. Prime among these are the increased expression of the DNA repair protein O6-guanine-DNA methyltransferase (MGMT) and cellular deficiency in DNA mismatch repair (MMR).

Therapeutic effect of NEO400, perillyl alcohol conjugated to linoleic acid, in a mouse model of UV-induced skin damage.

Excessive exposure to ultraviolet radiation (UVR) causes harmful effects on human skin. Pre-exposure application of sunscreen can be protective, but not after damage already has occurred. There is a need for agents that can be applied post-UVR exposure to repair the damage.

Activation of Epstein-Barr Virus' Lytic Cycle in Nasopharyngeal Carcinoma Cells by NEO212, a Conjugate of Perillyl Alcohol and Temozolomide.

The Epstein-Barr virus (EBV) is accepted as a primary risk factor for certain nasopharyngeal carcinoma (NPC) subtypes, where the virus persists in a latent stage which is thought to contribute to tumorigenesis. Current treatments are sub-optimal, and recurrence occurs in many cases. An alternative therapeutic concept is aimed at triggering the lytic cycle of EBV selectively in tumor cells as a means to add clinical benefit.

Enhancing brain entry and therapeutic activity of chimeric antigen receptor T cells with intra-arterial NEO100 in a mouse model of CNS lymphoma.

Objective: Malignancies of the CNS are difficult to treat because the blood-brain barrier (BBB) prevents most therapeutics from reaching the intracranial lesions at sufficiently high concentrations. This also applies to chimeric antigen receptor (CAR) T cells, for which systemic delivery is inferior to direct intratumoral or intraventricular injection of the cells. The authors previously reported on a novel approach to safely and reversibly open the BBB of mice by applying intra-arterial (IA) injections of NEO100, a pharmaceutical-grade version of the natural monoterpene perillyl alcohol.

Using machine learning and big data for the prediction of venous thromboembolic events after spine surgery: A single-center retrospective analysis of multiple models on a cohort of 6869 patients.

Objective: Venous thromboembolic event (VTE) after spine surgery is a rare but potentially devastating complication. With the advent of machine learning, an opportunity exists for more accurate prediction of such events to aid in prevention and treatment.

Methods: Seven models were screened using 108 database variables and 62 preoperative variables.

Inhibition of autophagy and induction of glioblastoma cell death by NEO214, a perillyl alcohol-rolipram conjugate.

Glioblastoma (GBM) is the most aggressive primary brain tumor, exhibiting a high rate of recurrence and poor prognosis. Surgery and chemoradiation with temozolomide (TMZ) represent the standard of care, but, in most cases, the tumor develops resistance to further treatment and the patients succumb to disease. Therefore, there is a great need for the development of well-tolerated, effective drugs that specifically target chemoresistant gliomas.

Reduced non-CpG methylation is a potential epigenetic target after spinal cord injury.

DNA methylation is a critical epigenetic regulator in the occurrence and development of diseases and is closely related to various functional responses in relation to spinal cord injury. To investigate the role of DNA methylation in spinal cord injury, we constructed a library with reduced-representation bisulfite sequencing data obtained at various time points (day 0-42) after spinal cord injury in mice. Global DNA methylation levels, specifically non-CpG (CHG and CHH) methylation levels, decreased modestly following spinal cord injury.

Intranasal Delivery of miR133b in a NEO100-Based Formulation Induces a Healing Response in Spinal Cord-Injured Mice.

Despite important advances in the pre-clinical animal studies investigating the neuroinhibitory microenvironment at the injury site, traumatic injury to the spinal cord remains a major problem with no concrete response. Here, we examined whether (1) intranasal (IN) administration of miR133b/Ago2 can reach the injury site and achieve a therapeutic effect and (2) NEO100-based formulation of miR133b/Ago2 can improve effectiveness. 24 h after a cervical contusion, C57BL6 female mice received IN delivery of miR133b/Ago2 or miR133b/Ago2/NEO100 for 3 days, one dose per day.

Enhanced brain entry of checkpoint-inhibitory therapeutic antibodies facilitated by intraarterial NEO100 in mouse models of brain-localized malignancies.

Objective: Immune checkpoint-inhibitory therapeutic antibodies have shown striking activity against several types of cancers but are less effective against brain-localized malignancies, in part due to the protective effect of the blood-brain barrier (BBB). The authors hypothesized that intraarterial (IA) delivery of a novel compound, NEO100, has the potential to safely and reversibly open the BBB to enable brain-targeted therapeutic activity of checkpoint-inhibitory antibodies.

Methods: Immunocompetent mice with syngeneic glioblastoma or melanoma cells implanted into their brains were subjected to a single IA injection of NEO100 to open their BBB.

NEO212, a Perillyl Alcohol-Temozolomide Conjugate, Triggers Macrophage Differentiation of Acute Myeloid Leukemia Cells and Blocks Their Tumorigenicity.

Many patients with acute myeloid leukemia (AML) are still dying from this disease. In the past, the alkylating agent temozolomide (TMZ) has been investigated for AML and found to be partially effective; however, the presence of O6-methylguanine DNA methyltransferase (MGMT; a DNA repair enzyme) in tumor cells confers profound treatment resistance against TMZ. We are developing a novel anticancer compound, called NEO212, where TMZ was covalently conjugated to perillyl alcohol (a naturally occurring monoterpene).

Detection of perillyl alcohol and its metabolite perillic acid in postsurgical glioblastoma tissue after intranasal administration of NEO100: illustrative case.

Background: Intranasal delivery of NEO100, a pharmaceutical-grade version of the natural monoterpene perillyl alcohol (POH), is undergoing clinical phase IIa testing as a treatment for glioblastoma (GBM). However, so far there is no evidence that intranasal delivery of NEO100 indeed results in POH reaching intracranial malignancies in a patient.

Observations: After surgical removal of her recurrent GBM tumor, a patient received daily intranasal NEO100 therapy for more than 3 years before a second recurrence emerged.

A Prospective, Cohort Study of SITOIGANAP to Treat Glioblastoma When Given in Combination With Granulocyte-Macrophage Colony-Stimulating Factor/Cyclophosphamide/Bevacizumab/Nivolumab or Granulocyte-Macrophage Colony-Stimulating Factor/Cyclophosphamide/Bevacizumab/Pembrolizumab in Patients Who Failed Prior Treatment With Surgical Resection, Radiation, and Temozolomide.

Background: Glioblastoma (GBM) is the most common primary, malignant brain tumor in adults and has a poor prognosis. The median progression-free survival (mPFS) of newly diagnosed GBM is approximately 6 months. The recurrence rate approaches 100%, and the case-fatality ratio approaches one.

Lumbar surgical drains do not increase the risk of infections in patients undergoing spine surgery.

Purpose: The aim of this study was to characterize if the use of surgical drains or length of drain placement following spine surgery increases the risk of post-operative infection.

Methods: Records of patients undergoing elective spinal surgery at a tertiary care center were collected between May 5, 2016 and August 16, 2018. Pre-operative baseline characteristics were recorded including patient's demographics and comorbidities.

The Monoterpenoid Perillyl Alcohol: Anticancer Agent and Medium to Overcome Biological Barriers.

Perillyl alcohol (POH) is a naturally occurring monoterpenoid related to limonene that is present in the essential oils of various plants. It has diverse applications and can be found in household items, including foods, cosmetics, and cleaning supplies. Over the past three decades, it has also been investigated for its potential anticancer activity.

Potentially Curative Therapeutic Activity of NEO212, a Perillyl Alcohol-Temozolomide Conjugate, in Preclinical Cytarabine-Resistant Models of Acute Myeloid Leukemia.

Despite progress in the treatment of acute myeloid leukemia (AML), the clinical outcome remains suboptimal and many patients are still dying from this disease. First-line treatment consists of chemotherapy, which typically includes cytarabine (AraC), either alone or in combination with anthracyclines, but drug resistance can develop and significantly worsen prognosis. Better treatments are needed.

Utilization of Discarded Surgical Tissue from Ultrasonic Aspirators to Establish Patient-Derived Metastatic Brain Tumor Cells: A Guide from the Operating Room to the Research Laboratory.

Patient-derived cells from surgical resections are of paramount importance to brain tumor research. It is well known that there is cellular and microenvironmental heterogeneity within a single tumor mass. Thus, current established protocols for propagating tumor cells in vitro are limiting because resections obtained from conventional singular samples limit the diversity in cell populations and do not accurately model the heterogeneous tumor.

In vivo CRISPR screening for novel noncoding RNA functional targets in glioblastoma models.

CRISPR (clustered regularly interspaced short palindromic repeat)-based genetic screens offer unbiased and powerful tools for systematic and specific evaluation of phenotypes associated with specific target genes. CRISPR screens have been utilized heavily in vitro to identify functional coding and noncoding genes in a large number of cell types, including glioblastoma (GB), though no prior study has described the evaluation of CRISPR screening in GB in vivo. Here, we describe a protocol for targeting and transcriptionally repressing GB-specific long noncoding RNAs (lncRNAs) by CRISPR interference (CRISPRi) system in vivo, with tumor growth in the mouse cerebral cortex.

Enhanced brain delivery and therapeutic activity of trastuzumab after blood-brain barrier opening by NEO100 in mouse models of brain-metastatic breast cancer.

Background: The antitumor efficacy of human epidermal growth factor receptor 2 (HER2)-targeted therapies, such as humanized monoclonal antibody trastuzumab (Herceptin®, Roche), in patients with breast-to-brain cancer metastasis is hindered by the low permeability of the blood-brain barrier (BBB). NEO100 is a high-purity version of the natural monoterpene perillyl alcohol, produced under current good manufacturing practice (cGMP) regulations, that was shown previously to reversibly open the BBB in rodent models. Here we investigated whether NEO100 could enable brain entry of trastuzumab to achieve greater therapeutic activity.