Funding Status: Minimally Funded

This grant has been minimally funded and can proceed with research.

Lorem Sit Amet Dolor
Researcher: Lorem Sit Amet

123 abc lane, Townsville, ZZ 00000, USA
Funding Progress: $§ / $§§§§§

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Targeted protein degradation for DIPG therapy
Translational
DIPG, Childhood (Brain Cancer)
Lay Summary

Childhood brain tumors are the second most common type of pediatric cancer, with overall survival and treatment related long-term side effects far worse compared to other children with solid tumors and haematological malignancies. The prognosis of brain tumors in children has improved over the past decades; however, one third of these patients cannot be cured. For high-grade gliomas such as diffuse intrinsic pontine gliomas, the most aggressive brain tumors in children, the prognosis is in fact even worse. Despite intensive multimodality treatment (surgery, chemo, and radiotherapy), refractory disease and relapse are frequent events. Thus, there is a clear need for improved therapy. One of the most exciting and emerging therapeutic strategy is to use the cells own “disposal” system to remove unwanted proteins, known as drivers for tumor development.  Recently, we identified the natural compound Obtusaquinone (OBT) to kill cancer cells, including DIPG, by inducing an overall stress response, while inhibiting DIPG growth in mouse models. Based on OBT, we developed a novel chimera for targeted protein degradation to remove one of the main drivers of DIPG, BRD4, leading to efficient killing of DIPG cells and inhibiting DIPG growth in mouse models. If successful, this proposal could provide a novel and improved therapeutic strategy for our young patients with DIPG, and other brain tumors, leading to an increase in their overall survival and improved quality of life.

 

 

Executive Summary

 

Diffuse intrinsic pontine gliomas (DIPG) are highly aggressive brain tumors found in an area of the brainstem called the pons, which controls many of the body’s most vital functions such as breathing, blood pressure, and heart rate. DIPG is the leading cause of pediatric death by brain tumor. Median survival after diagnosis is only 9 months, and 5-year survival is less than 1%. Unfortunately, complete surgical removal is not an option in the treatment of these tumors due to their extensively infiltrative nature and related severe neurological damages to the most vital functions of the body caused by the surgery. The only effective traditional limited-field radiation produces responses in more than 90% of DIPG patients but only transiently. Despite intensive multimodality treatment, refractory disease and relapses are frequent events in these tumors. Numerous trials to increase the dose of radiation have been performed and have not improved patient survival. Experimental chemo- and biologic agents in addition to radiation are actively investigated. More than 250 clinical trials have been conducted in the past decades and several trials evaluating new agents are either underway or have been recently completed but none of these trials have shown any benefit in the likelihood or the median length of survival. Thus, new agents that can be used for adjuvant DIPG therapy are desperately needed.  

The transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) plays a key role in maintaining cellular homeostasis in response to oxidative stress by regulating the expression of antioxidant response element (ARE)-dependent genes. Keap1 (Kelch-like ECH-associated protein 1) is recognized as a predominant negative regulator of Nrf2, and functions as a substrate adaptor protein for the ubiquitin ligase CRL3 (cullin 3 (CUL3)-RING ubiquitin ligase). During homeostasis, Keap1 recruits Nrf2 to CUL3 thereby promoting its ubiquitination and subsequent proteasomal degradation. We have previously identified the natural product obtusaquinone (OBT) as a potent antineoplastic agent with promising in vivo activity against adult and pediatric malignant gliomas, including DIPG. We have developed novel OBT analogs with improved pharmacological properties and shown that OBT is a thiol-reactive compound that reacts reversibly with cysteine residues, and particularly binds to Keap1, leading to CRL3-mediated autoubiquitination and proteasomal degradation of Keap1 thereby activating the Nrf2 pathway, while yielding an overall stress response. Based on the observation that OBT binds Keap1 and induces its proteasomal degradation, we hypothesized that OBT could be exploited as a novel ubiquitin ligase recruiting moiety for the design of next generation therapeutics. Targeted protein degradation, and particularly proteolysis-targeting chimera (PROTAC), holds a great promise as a novel therapeutic strategy to drug previously undruggable targets. This technology engages the cell’s own natural disposal system, known as the Ubiquitin/Proteasome System, to remove disease-causing proteins to treat difficult-to-treat pathologies. PROTACs hold great promise as a therapeutic strategy, but still suffers many limitations, including variable efficiency and poor brain penetrance.  We synthesized a chimera consisting of OBT and JQ1 separated by a linker. JQ1 is a well-established PROTACs ligand and a selective inhibitor of BRD4, an important regulator of glioma growth, specially DIPG. Our preliminary data shows that OBT-JQ1 induces nearly complete BRD4 proteasomal degradation in different patient-derived DIPG cells, as low as 30nM. Interestingly, we showed that OBT and JQ1 induces DIPG cell death in a synergistic manner. In this proposal, we will build on our previous studies and strong preliminary data and evaluate OBT-JQ1 as a dual functional drug for targeted protein degradation and induction of overall stress response, synergizing with JQ1 leading to DIPG cell death. Results will be validated in clinically-relevant patient-derived DIPG models which infiltrate the brain of mice similar to human tumors using different novel quantitative multiplexed bioluminescence imaging.

Description of Research Proposal

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Budget

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer gravida non felis non euismod. Fusce finibus aliquet consequat. Nam ac metus bibendum, iaculis purus sed, suscipit ligula. Proin et nisi libero. Mauris non urna urna. Nullam augue eros, fringilla sed mauris vitae, porta tincidunt risus. Aliquam sed tincidunt sem. Quisque lacinia quam tortor, imperdiet efficitur odio iaculis in. Sed ultricies condimentum volutpat. Vivamus dignissim faucibus porta.

Curabitur ut ipsum non odio malesuada vulputate. Morbi maximus, est eu lobortis molestie, tortor sapien hendrerit nisi, in cursus odio diam ut odio. Fusce pulvinar volutpat velit. Aliquam erat volutpat. Integer rhoncus mollis suscipit. Praesent non ipsum mollis, finibus nunc a, scelerisque nibh. In feugiat iaculis velit, eu semper lacus dignissim nec. Praesent vitae nisi leo. Cras venenatis dictum magna ut semper. Sed eget eros nibh. Sed vitae quam sed dolor faucibus elementum. Curabitur interdum porttitor finibus. Nullam tincidunt odio lectus, sit amet rhoncus libero dapibus sed. Sed mollis egestas enim, vel porta tortor volutpat eget.

Morbi orci urna, ornare non pretium eget, pulvinar eget magna. Ut consectetur efficitur varius. Fusce ac aliquet mauris, at mattis ligula. Quisque est libero, interdum id orci et, ornare luctus diam. Proin commodo lectus id accumsan blandit. Nulla eu turpis interdum, luctus ante ac, imperdiet tellus. In semper enim eu tristique aliquam.

Collaborations and Conflicts of Interest

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer gravida non felis non euismod. Fusce finibus aliquet consequat. Nam ac metus bibendum, iaculis purus sed, suscipit ligula. Proin et nisi libero. Mauris non urna urna. Nullam augue eros, fringilla sed mauris vitae, porta tincidunt risus. Aliquam sed tincidunt sem. Quisque lacinia quam tortor, imperdiet efficitur odio iaculis in. Sed ultricies condimentum volutpat. Vivamus dignissim faucibus porta.

Curabitur ut ipsum non odio malesuada vulputate. Morbi maximus, est eu lobortis molestie, tortor sapien hendrerit nisi, in cursus odio diam ut odio. Fusce pulvinar volutpat velit. Aliquam erat volutpat. Integer rhoncus mollis suscipit. Praesent non ipsum mollis, finibus nunc a, scelerisque nibh. In feugiat iaculis velit, eu semper lacus dignissim nec. Praesent vitae nisi leo. Cras venenatis dictum magna ut semper. Sed eget eros nibh. Sed vitae quam sed dolor faucibus elementum. Curabitur interdum porttitor finibus. Nullam tincidunt odio lectus, sit amet rhoncus libero dapibus sed. Sed mollis egestas enim, vel porta tortor volutpat eget.