Preclinical Studies on Polyunsaturated Fatty Acid-Taxoid Conjugate for IND Filing

用于 IND 申报的多不饱和脂肪酸-紫杉烷偶联物的临床前研究

• 批准号: 8149967
• 负责人: RAMESH CHANDER GUPTA
• 金额: $ 201.46万
• 依托单位: CHEM-MASTER INTERNATIONAL, INC
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-10 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8149967
• 关键词: Adverse effects; Animals; Area; Breast; Cancer cell line; Canis familiaris; Cell Death; Chemistry; Chemotherapy-Oncologic Procedure; Colon; Colon Carcinoma; Combined Modality Therapy; Cytotoxic Chemotherapy; Cytotoxic agent; DHA-Paclitaxel; Development; Disease; Docosahexaenoic Acids; Dose; Dose-Limiting; Drug Delivery Systems; Drug Kinetics; Drug resistance; Enzymes; Gastrointestinal tract structure; Generations; Goals; Growth; Hair; Half-Life; Health; Hemorrhage; Human; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Massachusetts; Maximum Tolerated Dose; Metabolism; Methods; Mission; Mucous Membrane; Nail plate; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Normal Cell; Omega-3 Fatty Acids; Organ; Paclitaxel; Pancreas; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Phenotype; Polyunsaturated Fatty Acids; Production; Qualifying; Rattus; Refractory; Roswell Park Cancer Institute; Route; SCID Mice; Schedule; Services; Site; Small Business Innovation Research Grant; Small Business Technology Transfer Research; Societies; Taxoids; Tissues; Toxic effect; Toxicology; Validation; Xenograft procedure; antitumor drug; base; cancer cell; cancer therapy; chemical synthesis; chemotherapeutic agent; chemotherapy; clinical toxicology; cytotoxic; design; docetaxel; drug development; experience; improved; innovation; malignant breast neoplasm; mouse model; neoplastic cell; phase 1 study; phase 2 study; pre-clinical; preclinical study; professor; programs; public health relevance; safety study; success; targeted delivery; therapeutic evaluation; tumor; tumor specificity; tumor xenograft

DESCRIPTION (provided by applicant): An unmet need in the area of cytotoxic therapy for human cancer is the development of an agent that is highly effective, yet is relatively safe with respect to side effects. The use of most chemotherapeutic drugs in human cancer treatment is accompanied by a variety of side effects including hair loss, corrugated and twisted nail formation and hemorrhage of the mucosa of the alimentary canal. The attractive aspects of DHA-SBT-1214 are its ability to target tumor cells then, once absorbed, release the cytotoxic taxoid moiety where it will do the most damage. This is the innovative aspect of this drug development program. Such a drug should readily find a place in the armamentarium of anti-tumor drug substances. With minimal side effects, it should also lend itself commercially to combination therapy in conjunction with an anti-tumor enzyme regulator, as is becoming the common practice in modern cancer treatment. Chem-Master's mission is to develop DHA-SB-T-1214 as efficacious and safer drug for cancer chemotherapy, especially against tumors that cannot effectively be treated by Taxol(R), docetaxel, Taxoprexin(R), and other commonly used chemotherapeutic drugs. In the SBIR Phase I study, we have made significant progress toward this goal. We have confirmed that the chemical synthesis of DHA-SBT-1214 with high purity is feasible at 10 g scale based on the proposed synthetic route. We have also confirmed the remarkable efficacy of DHA- SBT-1214 against pancreatic cancer (CFPAC-1) and non-small cell lung cancer (H460) xenografts in SCID mice models in addition to highly drug-resistant (Pgp+) colon cancer (DLD-1) xenograft as well as significant activity against another highly drug-resistant (Pgp+) breast cancer (LCC6-MDR) xenograft, wherein Taxol(R) and Taxoprexin(R) showed very limited activity or totally inactive. The project proposed in this Phase II application is designed to advance our studies on DHA-SBT-1214 to treat a variety of human tumors principally associated with colon, breast, lung and pancreatic cancers as well as to perform pre-clinical toxicology studies required for IDN filing and approval. Thus, the key technical objectives in the Phase II studies are (i) further expansion of the current studies to cancer cell lines that are more refractory to other cytotoxic agents and/or to faster growing tumors; (ii) Pharmacokinetics/pharmacodynamics (PK/PD) studies including half-life, distribution, metabolism and maximum tolerated dose, as well as all other pre-clinical toxicology studies necessary for IND filing; (iii) optimization of the preparative methods in 200 g scale for the reliable production of DHA-SBT-1214 in GMP and the development of validation methods for the various intermediates in the synthetic sequence. PUBLIC HEALTH RELEVANCE: The proposed project is of great relevance to human health. Currently there are no really effective drug substances that can abolish or even partially inhibit the growth of human colon cancer because this particular form of cancer over-expresses the MDR phenotype. Remarkably DHA-SBT-1214, an omega-3 fatty acid- taxoid conjugate, can penetrate these cancer cells selectively and by-pass the MDR apparatus, thereafter inducing cell death. The further development of DHA-SBT-1214 as a possible treatment for colon, pancreatic, lung, breast and other forms of cancer could scarcely be more relevant in a society where many forms of this multi-variate and largely untreatable disease, seem to be increasing.

描述（由申请人提供）：在人类癌症细胞毒治疗领域的一个未满足的需求是开发一种高效的药物，但在副作用方面相对安全。在人类癌症治疗中，大多数化疗药物的使用都伴随着各种副作用，包括脱发、指甲形成波纹和扭曲以及消化道粘膜出血。DHA-SBT-1214吸引人的地方在于它能够靶向肿瘤细胞，一旦被吸收，就会释放出细胞毒性类taxoid部分，在那里它会造成最大的伤害。这是这个药物开发项目的创新之处。这样的药物应该很容易在抗肿瘤药物的药库中找到一席之地。由于副作用很小，它还可以在商业上与抗肿瘤酶调节剂联合使用，这正在成为现代癌症治疗的普遍做法。Chem-Master的使命是开发DHA-SB-T-1214作为有效和更安全的癌症化疗药物，特别是针对紫杉醇（Taxol）、多西紫杉醇（docetaxel）、紫杉醇（Taxoprexin）和其他常用化疗药物无法有效治疗的肿瘤。在SBIR I期研究中，我们朝着这一目标取得了重大进展。我们已经证实，根据提出的合成路线，在10 g规模下化学合成高纯度的DHA-SBT-1214是可行的。我们还证实了DHA- SBT-1214在SCID小鼠模型中对胰腺癌（CFPAC-1）和非小细胞肺癌（H460）异种移植物的显著疗效，以及对另一种高度耐药（Pgp+）结肠癌（DLD-1）异种移植物的显著活性，其中紫杉醇(R)和Taxoprexin(R)表现出非常有限的活性或完全无活性。该II期申请项目旨在推进我们对DHA-SBT-1214的研究，以治疗主要与结肠癌、乳腺癌、肺癌和胰腺癌相关的多种人类肿瘤，并进行IDN申请和批准所需的临床前毒理学研究。因此，II期研究的关键技术目标是：(1)进一步扩大目前的研究范围，使其适用于对其他细胞毒性药物和/或对生长更快的肿瘤更难治的癌细胞系；（ii）药代动力学/药效学（PK/PD）研究，包括半衰期、分布、代谢和最大耐受剂量，以及IND申请所需的所有其他临床前毒理学研究；（iii）优化200 g规模的制备方法，使DHA-SBT-1214在GMP中可靠地生产，并开发合成序列中各种中间体的验证方法。