Validating the mode of action of ergosterol peroxide as a selective breast cancer inhibitor
验证过氧化麦角甾醇作为选择性乳腺癌抑制剂的作用方式
基本信息
- 批准号:10411072
- 负责人:
- 金额:$ 11.7万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-04-15 至 2026-03-31
- 项目状态:未结题
- 来源:
- 关键词:4T1AddressAffectAfrican AmericanAminoacyl-tRNA hydrolaseAnkyrin RepeatApoptosisBiologicalBiological AssayBiological AvailabilityBiomedical ResearchBiophysicsBreast Cancer CellBreast Cancer ModelBreast Cancer PatientBreast Cancer TreatmentCell DeathCell LineCell modelCellsCellular AssayCessation of lifeChemicalsCholesterolCholesterol HomeostasisClinicClinical ResearchClustered Regularly Interspaced Short Palindromic RepeatsComplexCytosolDataDependenceDevelopmentDiagnosisDiseaseDoseDoxycyclineDrug toxicityERBB2 geneEarly DiagnosisEnvironmentEnzymesErgosterolExcisionExtravasationFemaleFutureGenesGoalsHispanic AmericansHomeostasisImpairmentIn complete remissionKnowledgeLeadLigationMCF10A cellsMalignant NeoplasmsMembraneMitochondriaMitochondrial ProteinsModalityModelingMusNatural ProductsNormal CellNormal tissue morphologyOxidation-ReductionOxidative StressPathway interactionsPatient-derived xenograft models of breast cancerPatientsPeroxidesPharmacologyPrognosisPropertyProtacProteinsPuerto RicoRecurrenceResearchResistanceSafetyScientistSteroidsSterolsStructureStudentsSubstrate SpecificitySurvival RateSystemTestingTherapeuticTherapeutic AgentsToxic effectTumor VolumeUbiquitinUbiquitinationUnited StatesWomanXenograft procedureZinc Fingersaggressive breast canceranti-cancer therapeuticantiproliferative agentsbasecancer cellcancer subtypeschemotherapyclinically relevantefficacy testingfungusimprovedin vivoin vivo Modelinhibitormalignant breast neoplasmmisfolded proteinmitochondrial dysfunctionmortalitymouse modelmulticatalytic endopeptidase complexneoplastic cellnovelpharmacokinetics and pharmacodynamicspre-clinicalprotein aggregationprotein complexpublic health relevancestemstudent participationtargeted treatmenttriple-negative invasive breast carcinomatumor progressionunderrepresented minority studentuptakevalosin-containing proteinwomen of color
项目摘要
PROJECT SUMMARY
Triple Negative Breast Cancer (TNBC) is an aggressive and lethal breast cancer subtype more commonly
diagnosed on younger (<40y) women of color (Hispanics and African American), who are more likely to have
disease recurrence and who have an overall shorter survival. Furthermore, additional limitations (i.e. drug
toxicity, and therapy resistance) persist in the clinic for TNBC patients. Thus, a critical need exists to discover
more desirable targeted therapeutic modalities that selectively target TNBC tumor cells while leaving normal
cells unaffected, enhancing a complete response and reducing TNBC-associated mortality rates. Accordingly,
our goal is to reduce BC mortality by identifying unique vulnerabilities of TNBC that can be exploited through the
development of selective therapeutic agents. We recently identified the natural product ergosterol peroxide a
steroidal compound found in fungi, as a potent antiproliferative agent against TNBC cell models with little to no
effect on noncancerous cells. We demonstrated that EP is more potent towards TNBC than HER2-positive
models. EP induces ROS and apoptosis in TNBC cells and reduces tumor volume in TNBC models in vivo.
However, EP’s mode of action (MOA) remains to be defined. Extended periods of oxidative stress in the
mitochondria lead to accumulation of damaged proteins, which are normally removed by ubiquitination via the
VCP/ANKZF1 pathway. We have synthesized EP in gram scale and show that EP accumulates in the cytosol
and affects VCP and ANKZF1 interactions, raising the possibility that the VCP/ANKZF1 complex is targeted
during its assembly prior to arriving to the mitochondria. Thus, taking advantage of TNBC’s dependency on sterol
uptake, removal of misfolded proteins and altered redox homeostasis, we propose that EP serves as a
VCP/ANKZF1 complex protein-protein inhibitor (PPI). We hypothesize that EP targets the VCP/ANKZF1
complex, impairing the ability of cancer cells to clear damaged proteins and causing mitochondria dysfunction to
induce TNBC cell death. To test the hypothesis we will identify the mechanism by which EP targets the
VCP/ANKZF1 complex in TNBC models using biophysical assays and synthesized EP-probes (Aim 1). The
results from this Aim will validate that targeting VCP/ANKZF1 complex induces increases misfolded and
aggregated proteins, which lead to cancer cell death. We will determine the efficacy of EP using syngeneic
models injected with doxycycline inducible ANKZF1 silenced cells, and in TNBC PDXs. EP safety and bio-
availability will also be determined and studied by MTD and PK/PD (Aim 2). The result of this aim will provide
data needed for the next step towards the translational development of EP. Student participation in this
hypothesis-driven research will improve the pipeline for URM students in biomedical research and lead to
improved BC treatment.
项目总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Michelle M Martínez其他文献
Pharmacological zinc and phytase supplementation enhance metallothionein mRNA abundance and protein concentration in newly weaned pigs.
药理学锌和植酸酶补充剂可增强刚断奶仔猪的金属硫蛋白 mRNA 丰度和蛋白质浓度。
- DOI:
- 发表时间:
2004 - 期刊:
- 影响因子:0
- 作者:
Michelle M Martínez;G. Hill;J. Link;N. Raney;R. Tempelman;C. Ernst - 通讯作者:
C. Ernst
Michelle M Martínez的其他文献
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{{ truncateString('Michelle M Martínez', 18)}}的其他基金
Validating the mode of action of ergosterol peroxide as a selective breast cancer inhibitor
验证过氧化麦角甾醇作为选择性乳腺癌抑制剂的作用方式
- 批准号:
10610422 - 财政年份:2022
- 资助金额:
$ 11.7万 - 项目类别:
INVESTIGATION OF REISHI AS A NATURAL THERAPEUTIC FOR INFLAMMATORY BREAST CANCER
灵芝作为炎性乳腺癌天然疗法的研究
- 批准号:
8357105 - 财政年份:2011
- 资助金额:
$ 11.7万 - 项目类别:
INVESTIGATION OF REISHI AS A NATURAL THERAPEUTIC FOR INFLAMMATORY BREAST CANCER
灵芝作为炎性乳腺癌天然疗法的研究
- 批准号:
8166209 - 财政年份:2010
- 资助金额:
$ 11.7万 - 项目类别:
INVESTIGATION OF REISHI AS A NATURAL THERAPEUTIC FOR INFLAMMATORY BREAST CANCER
灵芝作为炎性乳腺癌天然疗法的研究
- 批准号:
8573333 - 财政年份:1997
- 资助金额:
$ 11.7万 - 项目类别:
INVESTIGATION OF REISHI AS A NATURAL THERAPEUTIC FOR INFLAMMATORY BREAST CANCER
灵芝作为炎性乳腺癌天然疗法的研究
- 批准号:
8573407 - 财政年份:
- 资助金额:
$ 11.7万 - 项目类别:
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