# Determining the effects of bone morphogenetic protein receptor 2 (BMPR2) inhibition on neural stem cell neurogenesis and regulation of energy homeostasis in Alzheimer’s disease and cancer

> **NIH NIH R01** · RBHS -CANCER INSTITUTE OF NEW JERSEY · 2020 · $389,236

## Abstract

PROJECT SUMMARY
 Bone morphogenetic proteins (BMP) are highly expressed in lung cancer cells promoting survival and
distant spread. Increased BMP expression also occurs in the brain with natural aging and is accelerated in
Alzheimer’s disease (AD). BMP promotes the differentiation of adult neural stem cells (NSC) into astroglial
cells and suppresses their differentiation into neurons, which are required for memory and cognition. Inhibition
of the BMP receptors promotes the regeneration of new neurons and improves cognition in aging mice and
mouse models of AD.
 In our parent R01, we are developing BMPR2 inhibitors for the treatment of lung cancer. We have
developed significantly more specific BMPR2 inhibitors. We find that inhibition of BMPR2 causes potent
inhibition of mechanistic target of rapamycin 1 (mTORC1), mTORC2, and Akt. Furthermore, these novel
BMPR2 inhibitors cause the activation of AMP-activated protein kinase (AMPK). The inhibition of mTOR and
the activation of AMPK have not only been shown to suppress tumor growth but this same regulatory signature
has been shown to increase longevity and to decrease neurodegenerative diseases.
 Targeting BMPR2 represents a novel strategy to treat AD and other neurodegenerative diseases by
promoting neurogenesis. Neurodegenerative diseases and cancer are diseases of aging. The ability to slow
the aging process is a potential way to significantly delay the onset of neurodegenerative diseases, cancer,
and cardiovascular disease. Limiting caloric intake has been shown to increase longevity and impact the
development and treatment of age-related diseases including AD. The cellular response to caloric restriction
(CR) is dependent on the activation of AMPK and suppression of mTOR signaling, which is the same
regulatory signature induced by our BMPR2 inhibitors. A drug that can induce the biologic response mimicking
CR could have a major impact on age-related diseases.
 We hypothesize that BMPR2 inhibition with small molecules can be used to treat neurodegenerative
diseases and cancer, which involves the suppression of mTOR and the activation of AMPK. We have
established a team of scientists with expertise in BMP biology, BMP receptor trafficking, neuroscience,
medicinal chemistry, computational biology, neural pathology, and crystallography who together, are uniquely
qualified to successfully complete the following specific aims.
Aim 1: Determine in SAMP8 mouse models of Alzheimer’s disease, the effects of our new generation
of BMPR2 inhibitors engineered to cross the blood-brain barrier on NSC neurogenesis, synaptic and
dendritic integrity, and astrocyte senescence.
Aim 2: Determine in C. elegans the regulation of AMPK and mTOR with BMPR2 during starvation.
Examine whether AMPK and mTOR regulate daf-4(BMPR2) trafficking during starvation.

## Key facts

- **NIH application ID:** 10120126
- **Project number:** 3R01CA225830-03S1
- **Recipient organization:** RBHS -CANCER INSTITUTE OF NEW JERSEY
- **Principal Investigator:** JOHN LANGENFELD
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $389,236
- **Award type:** 3
- **Project period:** 2018-07-06 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10120126

## Citation

> US National Institutes of Health, RePORTER application 10120126, Determining the effects of bone morphogenetic protein receptor 2 (BMPR2) inhibition on neural stem cell neurogenesis and regulation of energy homeostasis in Alzheimer’s disease and cancer (3R01CA225830-03S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10120126. Licensed CC0.

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