Targeting Oncogenic Drivers in Cancer

针对癌症的致癌驱动因素

• 批准号: 10228096
• 负责人: Matthew W Boudreau
• 金额: $ 4.6万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2022-03-06
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10228096
• 关键词: Accounting; Address; Alleles; Allelic Imbalance; Aromatase Inhibitors; Biological; Biological Availability; Biological Models; Brain; CTNNB1 gene; Cancer Biology; Cell Death; Cell Line; Cells; Clinic; Clinical; Clinical Oncology; Clinical Trials; Coin; Complex; Cytostatics; Cytotoxic agent; Data; Data Set; Development; Disease; Disease Management; Disease Resistance; Doxycycline; Drug Kinetics; Estrogen Receptor alpha; Estrogen Therapy; Estrogens; Evaluation; Generations; Growth; Incidence; Investigation; Lead; Link; Lung; Malignant Neoplasms; Malignant neoplasm of liver; Mammary Neoplasms; Measures; Mediating; Metabolism; Metastatic breast cancer; Metastatic malignant neoplasm to brain; Modality; Modeling; Mutation; Neoplasm Metastasis; Nitrogen; Normal Cell; Normal tissue morphology; Oncogenes; Oncogenic; Oral; Pathway interactions; Patients; Penetrance; Pharmaceutical Chemistry; Pharmacodynamics; Phase; Phase I Clinical Trials; Plant Roots; Positioning Attribute; Primary carcinoma of the liver cells; Property; Proteins; Proteomics; Resistance; Sampling; Selective Estrogen Receptor Modulators; Signal Transduction; Testing; Therapeutic; Toxic effect; Training; Work; addiction; anti-cancer; base; beta catenin; blood-brain barrier penetration; bone; cancer cell; cancer therapy; cancer type; career; clinical development; complex data; cytotoxic; driver mutation; drug discovery; experience; experimental study; gain of function; genomic data; in vivo; insight; malignant breast neoplasm; metabolic abnormality assessment; metabolomics; mortality; mouse model; mutant; neurotoxicity; novel; overexpression; resistance mechanism; response; skills; small molecule; success; targeted treatment; therapeutic target; therapy resistant; tumor; tumor eradication; tumor growth; tumor metabolism

Project Summary & Abstract Targeting estrogen receptor alpha (ERα) is a major anticancer strategy in the treatment of ERα-positive breast cancer. However, current targeted therapies for ERα have only cytostatic activity and do not induce rapid quantitative killing of cancer cells, ultimately leading to resistance. A major resistance mechanism is ERα mutation leading to constitutively activation that drives tumor growth and metastasis, with Y537S and D538G accounting for the majority of driver mutations. These resistant tumors maintain overexpression of ERα, suggesting an opportunity to develop novel small molecules that can leverage aberrant ERαWT/Mut expression. We have discovered one such compound, ErSO, that has profound cytotoxic activity against ERαWT/Mut positive cancer cells, via rapid activation of the ERαWT/Mut-dependent anticipatory unfolded protein response (aUPR). The power of this cytotoxic activity has been observed with multiple examples of complete eradications of ERαWT/Mut-positive breast tumors in orthotopic and metastatic murine models. While there is a high translational potential for ErSO with a Phase 1 clinical trial planned for 2020, herein we discuss features of ErSO that demonstrate ErSO may only be an ideal candidate treating brain metastases. There is ample need for a second- generation ErSO with better pharmacokinetic properties and safer toxicity profile for the treatment of ERα- positive cancer. Planned work (F99 phase) consists of synthesizing more polar derivatives of ErSO, which will be assessed in mechanistic studies, in vivo tolerability, blood-brain barrier penetration, and efficacy models. These second generation compounds will likely have increased bioavailability, minimal neurotoxicity, and a safer toxicity profile, enabling their translational potential for addressing the treatment of ERα-positive cancer. While targeted anticancer therapy has altered the clinical landscape for challenging cancers, hepatocellular carcinoma (HCC) remains highly lethal with a rising mortality and incidence rate. HCC is vastly heterogenous disease with the only conserved driver mutations found in TERT and CTNNB1, which currently lie in the ‘undruggable’ target space. Herein, I describe efforts study CTNNB1 mutant allele imbalance (MAI) as a measure of CTNNB1 oncogenic addiction and propose in-depth cellular studies to annotate the impact of CTNNB1 MAI on oncogenic metabolism (K00 Phase). This exploration will provide insights into potential therapeutic targets for the treatment of HCC. These F99/K00 proposals seek produce a well-rounded, in-depth skill set to prepare me for success as an independent PI. Specifically, the F99 proposed work will refine my work in drug discovery and small molecule development. Planned K00 work will expand my expertise with new experiences in managing complex data sets to elucidate conclusions about fundamental cancer biology. Completion of this training will produce a powerful basis for my career in developing novel translational solutions for clinical oncology.

项目摘要及摘要