Making New Neurons When You Need Them

Western societies are aging societies, and the incidence of dementias, Alzheimer’s disease, and other diseases of the aged are on the rise. Treatments for these conditions are largely supportive, but being able to make new neurons to replace the ones that have died is almost certainly where it’s at.

At INSERM and CEA in Marseille, France, researchers have shown that chemicals that block the activity of a growth factor called TGF-beta improves the generation of new neurons in aged mice. These findings have spurred new investigations into compounds that can enable new neuron production in order to mitigate the symptoms of neurodegenerative diseases. Such treatments could also restore the cognitive abilities of those who have suffered neuron loss as a result of radiation therapy or a stroke.

The brain forms new neurons regularly to maintain our cognitive abilities, but aging or radiation therapy to treat tumors can greatly perturb this function. Radiation therapy is the adjunctive therapy of choice for brain tumors in children and adults.

Various studies suggest that the reduction in our cache of neurons contributes to cognitive decline. For example, exposure of mice to 15 Grays of radiation is accompanied by disruption to the olfactory memory and reduction in neuron production. A similar event occurs as a result of aging, but in human patients undergoing radiation treatment, cognitive decline is accelerated and seems to result from the death of neurons.

How then, can we preserve the cache of neurons in our brains? The first step is to determine the factors responsible for the decline is neuron production. In contrast to contemporary theory, neither heavy doses of radiation nor aging causes completely destruction of the neural stem cells that can replenish neurons. Even after doses of radiation and aging, neuron stem cell activity remains highly localized in the subventricular zone (a paired brain structure located in the outer walls of the lateral ventricles), but they do not work properly.

Subventricular Zone
Subventricular Zone

Experiments at the INSERM and CEA strongly suggest that in response to aging and high doses of radiation, the brain makes high levels of a signaling molecule called TGF-beta, and this signaling molecule pushes neural stem cell populations into dormancy. This dormancy also increases the susceptibility of neural stem cells into apoptosis.

Marc-Andre Mouthon, one of the main authors of this research, explained his results in this manner: “Our study concluded that although neurogenesis is reduced in aging and after a high dose of radiation, many stem cells survive for several months, retaining their ‘stem’ characteristics.”

Part two of this project showed that blocking TGFbeta with drugs restored the production of new neurons in aging or irradiated mice.

Thus targeted therapies that block TGFbeta in the brains of older patients or cancer patients who have undergone high dose radiation for a brain tumor might reduce the impact of brain lesions caused by such events in elderly patients who show distinct signs of cognitive decline.


Geron Corporation Announces Phase II Trial for Brain-Specific Anticancer Drug GNR1005

After a successful completion of a Phase I study, Geron Corporation announces the initiation of a phase II trial for its GRN1005 anticancer drug. This drug was designed to specifically treat tumors that have metastasized (spread) to the brain from the lung. This clinical trial is called GRABM-L, which stands for GRN1005 Against Brain Metastases – Lung cancer). This phase II trial is designed to determine the efficacy of GRN1005 in patients with brain metastases arising from non-small cell lung cancer (NSCLC).

GRN1005 is a novel cancer drug that consists of three molecules of the anticancer drug paclitaxel linked to a 19 amino acid peptide (Angiopep-2). This 19-amino acid peptide binds to a receptor called the “lipoprotein receptor-related protein 1” (LRP1), which is one of the most highly expressed receptors on the surface of the blood-brain barrier (BBB). Brain tumor treatment is exceedingly difficult because the central nervous system is surrounded by the BBB. The BBB prevents molecules from entering the brain unless they can bind specific receptors. When GRN1005 binds to the LRP1 receptor, the binding facilitates “receptor-mediated transport,” or transcytosis, across the BBB into the brain tissue. Conveniently, LRP1 is also very heavily expressed in many tumors. Therefore, once GRN1005 enters the brain, it can gain entry into tumor cells. GRN1005 is a “prodrug,” which means that the form that the patient takes is inactive, but the drug becomes active once it enters cells and is cleaved by enzymes called “esterases” to release active paclitaxel from the peptide.

Geron’s Executive Vice President, Head of R&D and Chief Medical Officer, Stephen M. Kelsey, M.D., said: “With the treatment of the first patient in the GRABM-L study, we have initiated both of the planned Phase 2 clinical trials of GRN1005 in patients with cancer metastases in the brain, a significant unmet medical need for which there are currently no approved drug therapies. We have been encouraged by the preliminary evidence of anti-tumor activity against brain metastases observed in the Phase 1 study of GRN1005, and we hope to confirm these results in our Phase 2 trials.”

The purpose of GRABM-L Phase 2 study is to determine the efficacy, safety and tolerability of GRN1005 in patients with brain metastases from Non-Small Cell Lung Cancer. The trial plans to enroll 50 patients, who will receive one intravenous dose of GRN1005 every three weeks (650 mg/m2). The primary efficacy endpoint for the trial is the response of the tumors to the drug during the course of treatment.

Patients with brain cancer, particularly secondary tumors that are the result of metastases, currently have few options. The reason for this treatment dead-end is the difficulty in getting antitumor drugs to effectively cross the blood-brain barrier and enter the tumor. Preclinical and Phase 1 data indicate that GRN1005 not only transports paclitaxel into tumors inside the brain through LRP1-mediated transport, but also has activity against tumors outside the brain.

Data on safety and tolerability, and preliminary evidence of anti-tumor activity of GRN1005 were documented in two separate Phase 1 multi-center, open-label, dose escalation clinical trials, conducted by Angiochem, Inc. In these trials, patients with heavily pre-treated progressing, advance-stage solid tumors and brain metastases (n=56; including NSCLC) and patients with recurrent or progressive malignant glioma (n=63) were treated with GRN1005. Final data were presented at the 2011 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in November. The data were encouraging. In patients with brain metastases from solid tumors, overall response rate was 20% (4/20) by one-dimensional assessment when treated with a dose of 650 mg/m2 of GRN1005 administered as single-agent therapy once every three weeks. Anti-tumor activity was observed against metastases inside the brain and in organs outside the brain, such as the liver, lung and lymph nodes.

Geron’s clinical development plan for GRN1005 includes two Phase 2 clinical trials in patients with brain metastases arising from either breast cancer (GRABM-B) or non-small cell lung cancer (GRABM-L). Top-line data from both studies are expected to be available by the end of the second quarter of 2013.