Lorem Sit Amet Dolor
123 abc lane, Townsville, ZZ 00000, USA
Funding Progress: $§ / $§§§§§
Epigenetic Targeted Therapy and Resistance in AT/RT
TranslationalAtypical Teratoid/Rhabdoid Tumor, Childhood (Brain Cancer)
Lay Summary
Pediatric rhabdoid tumor in the brain, atypical teratoid/rhabdoid tumor (AT/RT), is a highly malignant brain tumor that has a very poor prognosis despite aggressive treatment. The development of new, effective therapeutic approaches for AT/RT has been hindered by a lack of specific therapeutic targets. It is necessary to find effective therapeutic targets, preferably based on the understanding of the molecular mechanisms that promote this highly malignant brain tumor. A tumor suppressor gene (SMARCB1) is absence in the majority of AT/RT and loss of this gene leads to increase activity of histone binding proteins and promote tumor growth. This research involving pharmacologic inhibition of histone binding proteins, EZH2 and BRD4, is of high importance for developing effective therapies for AT/RT, as recently published results, indicate the abnormal activity of the histone binding proteins (EZH2 and BRD4) with absence of tumor suppressor gene (SMARCB1) as being of fundamental importance to the occurrence of AT/RT. Major goal of this project is to determine whether therapeutic combination of targeting histone binding proteins, BRD4 and EZH2, provides synergistic benefits, and will inform how best to maximize the clinical potential of combination therapy for effective treatment of children with AT/RT. This research will also test how tumor adapt to molecular targeted therapy, that will ultimately inform clinicians how to treat tumors that have resistance to molecular targeted therapy. Finally, this project will explore how our combination therapy interacts with radiation in treating AT/RT, which is important due to the frequent use of radiation in treating AT/RT.
Executive Summary
Pediatric rhabdoid tumors in the central nervous system (CNS), atypical teratoid/rhabdoid tumors (AT/RTs), are quite possibly the most malignant and lethal of all primary brain tumors in children, and are especially devastating since their occurrence is largely restricted to very young patients. The development of novel, effective therapeutic approaches for AT/RT has been hindered by a lack of specific therapeutic targets for this polymorphic tumor. It is necessary to define effective therapeutic targets, preferably based on the understanding of the molecular mechanisms that promote aggressive biological behavior of this disease.
SMARCB1 is a tumor suppressor gene biallelically inactivated in the majority of AT/RT. The absence of SMARCB1 promotes increased EZH2 methyltransferase activity that generally suppresses gene transcription through increased methylation of histone H3K27. Although SMARCB1 deficiency results in a net increase in H3K27 methylation across AT/RT genomes, there are nonetheless specific regions of the genome and specific genes in which H3K27 residues are acetylated, which requires bromo- and extra-terminal domain (BET) protein activity. H3K27 acetylation promotes gene expression, and the net gain in nuclear H3K27 methylation that is associated with SMARCB1 inactivation is therefore region- and gene specific in AT/RT cells. The aberrant activity of these H3K27 modifiers is of fundamental importance to the occurrence of AT/RT, and each is potentially an actionable therapeutic target for treating AT/RT. Our preliminary results support the anti-tumor activity of EZH2 and BET bromodomain-containing protein 4 (BRD4) inhibitors in treating AT/RT. The primary goal of this project is to determine whether targeted inhibition of EZH2 and BET BRD4 activity has potential for improving treatment outcomes for AT/RT patients. We will test the hypothesis that loss of SMARCB1 alters H3K27 methylation and acetylation to promote cell growth through selective gene repression and activation at specific chromatin regions and genes in AT/RT genomes, while at the same time conferring cell sensitivity to targeted inhibition of EZH2 and BET BRD4 activity.
Research involving genetic and pharmacological inhibition of EZH2 and BRD4 in AT/RT is of high importance for establishing actionable targets for treating AT/RT (Aim1). We will identify differentially expressed RNA transcripts and corresponding proteins that may, themselves, be actionable. By determining whether combination treatments with EZH2 and BRD4 inhibitors affect the growth of AT/RT xenografts (Aim2a), this research will determine whether combination of two histone modifiers provides synergistic benefits as well as reducing the likelihood of drug resistance, and will inform how best to maximize the clinical potential of epigenetic combination therapy for effective treatment of children with AT/RT. We consider it likely that this combination treatment will increase the length of time for tumors to adapt to treatment. Nonetheless, we anticipate eventual tumor adaptation and acquisition of resistance to the combination treatment, and this research will reveal tumor adaptive mechanisms that will ultimately inform clinicians how to treat tumors that have acquired resistance to histone modifier therapy (Aim 2b). The information obtained from Aim 2b research is significant because cancer cell compensatory mechanisms for responses to sustained histone modifier treatment is unexplored, and results from this research will influence the efforts of others who are investigating therapeutics targeting histone modifiers. We have established and acquired nine patient-derived AT/RT cell lines and orthotopic AT/RT xenograft models including four cell lines developed in Northwestern University (NUH cell lines) (Table 1). These AT/RT cells produce rapidly growing tumors with dissemination patterns that recapitulate the invasive growth and CNS spread of AT/RT in patients and each has been modified with a luciferase reporter to enable in vivo bioluminescence imaging (BLI), that are amenable to complete the proposal research aims. This research will also explore how our epigenetic combination therapy interacts with radiation in treating AT/RT, which is important due to the frequent use of radiation and will help determine how best to use a novel therapeutic, in a clinical setting, for treating a currently incurable pediatric rhabdloid tumor.
Successful results from this proposal will facilitate informed actionable therapeutic targets, which, in turn, would support accelerated approval for the agents in the adjuvant setting, in a phase-1/phase-2 treatment design, given the high unmet need (no effective therapeutic agents known for this patient population) and orphan disease status.
Description of Research Proposal
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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.
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Sed at tortor et tortor tincidunt feugiat id in dui. Vivamus eget justo nisl. Aenean congue laoreet nisl a elementum. Nunc consectetur velit non ligula sollicitudin, quis eleifend urna sollicitudin. Sed tincidunt, nisl quis varius venenatis, dui massa condimentum tellus, sed sollicitudin diam magna mollis augue. Sed venenatis commodo purus id malesuada. Aenean volutpat elit vel gravida consectetur. Vestibulum diam quam, lacinia ac tortor eget, tincidunt dapibus dui. Pellentesque habitant morbi tristique senectus et netus et malesuada fames ac turpis egestas. Proin nisl leo, pretium sed arcu imperdiet, hendrerit sollicitudin sem. Duis non magna at nunc sagittis ullamcorper a id est. Maecenas cursus nisl in faucibus hendrerit.
Sed hendrerit vitae purus et tempor. Aenean vitae varius velit. Nullam aliquet ipsum elit. Mauris vestibulum purus et metus imperdiet, quis gravida eros pretium. Curabitur rutrum nunc vitae tincidunt condimentum. Aenean sit amet augue velit. Nunc tristique quis lorem id pharetra. Pellentesque sollicitudin, eros sed egestas rutrum, nulla nisl sodales elit, ut imperdiet nunc lectus sit amet nulla. Ut malesuada finibus libero. Curabitur mi dolor, sollicitudin quis bibendum quis, dictum sed enim.
Pellentesque nibh erat, egestas sit amet sagittis malesuada, rhoncus at neque. Mauris maximus commodo tortor, non egestas magna finibus vitae. Sed hendrerit nulla vel venenatis tempor. Suspendisse tristique tincidunt libero et placerat. Nam tincidunt condimentum lorem, vel pharetra est iaculis sed. Nullam ac tincidunt orci. Quisque pharetra ut sem sit amet aliquam. Phasellus risus libero, varius in condimentum vel, commodo id ipsum. Aliquam in metus cursus, mattis diam ut, aliquam magna. Suspendisse facilisis dui et orci varius, suscipit facilisis augue dapibus. In eget nibh ipsum. Suspendisse eget pharetra est, quis condimentum felis. Fusce scelerisque congue libero, sed aliquam mi elementum a. Etiam scelerisque ante non auctor porta. Nam eu nunc id ex finibus dictum. Praesent dui ex, dictum ac massa eget, rutrum gravida nisi.
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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.