Orally available transition state inhibitors for triple negative breast cancer

口服过渡态抑制剂治疗三阴性乳腺癌

• 批准号: 8646623
• 负责人: Steven Isaacman
• 金额: $ 22.5万
• 依托单位: NANOMETICS, LLC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8646623
• 关键词: Accounting; Affinity; Antineoplastic Agents; Biochemical Pathway; Biotechnology; Canis familiaris; Clinical; Colon Carcinoma; DNA Methylation; Data; Development; Diagnosis; Disease; Dose; Enzymes; Epidermal Growth Factor Receptor; Estrogen Receptors; Folate; Funding; Goals; Growth; Guidelines; Head and neck structure; Human; Knowledge; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Malignant neoplasm of lung; Malignant neoplasm of prostate; Marketing; Methylation; Modeling; Mus; Muscle Form Glycogen Phosphorylase; Oral; Ornithine Decarboxylase; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacotherapy; Phase; Phosphorylases; Polyamines; Preparation; Primary Neoplasm; Progesterone Receptors; Rattus; Recruitment Activity; Regimen; Relapse; Reporting; Research; Research Design; Risk; Small Business Technology Transfer Research; Staging; Survival Rate; Technology; Testing; Therapeutic; Toxic effect; United States National Institutes of Health; Work; Xenograft Model; anti-cancer therapeutic; breast cancer diagnosis; cancer therapy; commercial application; commercialization; improved; inhibitor/antagonist; innovation; intraperitoneal; malignant breast neoplasm; mouse model; new therapeutic target; novel; outcome forecast; pre-clinical; preclinical study; public health relevance; research clinical testing; research study; small molecule; success; technological innovation; triple-negative invasive breast carcinoma; tumor; tumor growth

Problem to be Solved: Triple-negative breast cancer (TNBC) is a deadly disease that accounts for 15-20% of all diagnosed breast cancers worldwide. Metastatic relapse of TNBC carries a poorer prognosis and lower survival rate compared to other breast cancer subtypes. Therefore, identifying novel targets and new therapeutics to treat patients diagnosed with TNBC remains a significant priority of the National Institutes of Health. Product and Long-Term Goal: Nanometics is developing a once daily, oral therapeutic, dubbed "MTDIA" for the treatment of TNBC. MTDIA inhibits a novel target, 5
-methylthioadenosine phosphorylase (MTAP), and disrupts biochemical pathways crucial for cancer growth. Technical Innovation: The MTAP enzyme is a promising new target for anti-cancer therapeutics because its systemic inhibition results in the whole-body accumulation of the 5'-methylthioadenosine (MTA) metabolite, which alters known anti-cancer pathways. Oral dosing with MTDIA is effective against both MTAP-positive and MTAP-negative tumors, causing a significant reduction in primary tumor growth rates and regression of existing tumors. Phase I Hypotheses: The hypotheses that will be tested during the Phase I STTR experiments are that: 1) clinically efficacious oral doses of MTDIA will be tolerable (non-toxic) in rat models, and 2) MTDIA will suppress tumor growth rates in rats with similar efficacy as demonstrated in mice (see Preliminary Results). Specific Aims: The specific aims of this Phase I STTR are to: 1) determine that pharmacologically relevant oral doses of MTDIA are non-toxic and tolerable in rats, and 2) determine that MTDIA suppresses TNBC tumors in rats to the same extent as has been demonstrated in mouse models. Phase II: Phase II STTR studies will establish toxicity of MTDIA in rats and beagle dogs under GLP guidelines. Commercial Opportunity: The global market for breast cancer therapeutics is forecast to reach $13.86 billion by 2017. Because the treatment options for metastatic relapse of TNBC are limited, there remains a significant need for new drugs that work through novel modes of action.

有待解决的问题：三阴性乳腺癌(TNBC)是一种致命的疾病，占 全世界所有被诊断为乳腺癌的人。转移性复发的TNBC预后较差且较低 生存率与其他乳腺癌亚型比较。因此，识别新的目标和新的 治疗被诊断为TNBC的患者仍然是美国国立卫生研究院的重要优先事项 健康。 产品和长期目标：Nanometics正在开发一种每日一次的口服治疗药物，名为“MTDIA” TNBC的治疗。MTDIA抑制一个新的靶点，5-甲硫腺苷磷酸化酶(MTAP)，以及 扰乱对癌症生长至关重要的生化途径。 技术创新：MTAP酶是抗癌治疗的一个有前途的新靶点，因为它 全身抑制导致5‘-甲硫腺苷(MTA)代谢物在全身积累， 这改变了已知的抗癌途径。口服MTDIA对MTAP阳性和 MTAP阴性肿瘤，导致原发肿瘤生长率显著降低，并导致 现有的肿瘤。 第一阶段假设：在第一阶段STTR实验中将检验的假设是：1) 临床上有效的口服剂量的MTDIA在大鼠模型中是可以耐受的(无毒的)，2)MTDIA将抑制 大鼠的肿瘤生长速度与在小鼠身上显示的效果相似(见初步结果)。 具体目标：这一阶段STTR的具体目标是：1)确定与药物相关的 口服剂量的MTDIA对大鼠无毒和耐受性，以及2)确定MTDIA抑制TNBC 大鼠肿瘤的程度与在小鼠模型中显示的相同。 第二阶段：第二阶段STTR研究将根据GLP指南确定MTDIA对大鼠和比格犬的毒性。 商机：全球乳腺癌治疗药物市场规模预计将达到138.6亿美元 到2017年。由于TNBC转移性复发的治疗选择有限，因此仍有显著的 需要通过新的作用模式发挥作用的新药。