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

描述(由申请人提供)：在人类癌症的细胞毒治疗领域，一个尚未得到满足的需求是开发一种高效的药物，但就副作用而言，它相对安全。大多数化疗药物在人类癌症治疗中的使用都伴随着各种副作用，包括脱发、皱纹和扭曲的指甲形成以及消化道粘膜出血。DHA-SBT-1214的吸引人的方面是它能够靶向肿瘤细胞，一旦被吸收，就会释放出细胞毒性紫杉醇部分，在那里它会造成最大的损害。这是这一药物开发计划的创新方面。这样的药物应该很容易在抗肿瘤药物物质的宝库中找到一席之地。在副作用最小的情况下，它还可以与抗肿瘤酶调节剂一起用于商业上的联合治疗，这正成为现代癌症治疗的常见做法。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(R)、多西紫杉醇、紫杉醇(R)和其他常用化疗药物无法有效治疗的肿瘤。在SBIR第一阶段研究中，我们在实现这一目标方面取得了重大进展。基于所提出的合成路线，我们证实了高纯度DHA-SBT-1214的化学合成在10g规模上是可行的。我们还证实了DHA-SBT-1214对SCID小鼠模型中的胰腺癌(CFPAC-1)和非小细胞肺癌(H460)移植瘤的显著疗效，以及对另一种高度耐药(PGP+)乳腺癌(LCC6-MDR)移植瘤的显著作用，其中紫杉醇(R)和泰素(R)活性非常有限或完全无效。在此第二阶段申请中提出的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各种人类肿瘤，并进行IDN备案和批准所需的临床前毒理学研究。因此，第二阶段研究的主要技术目标是：(1)将当前研究进一步扩大到对其他细胞毒剂和/或生长更快的肿瘤更具耐受性的癌细胞系；(2)药代动力学/药效学(PK/PD)研究，包括半衰期、分布、代谢和最大耐受量，以及IND申报所需的所有其他临床前毒理学研究；(3)优化200克规模的制备方法，以可靠地生产GMP中的DHA-SBT-1214，并制定合成序列中各种中间体的验证方法。 公共卫生相关性：拟议的项目与人类健康密切相关。目前还没有真正有效的药物物质可以消除甚至部分抑制人类结肠癌的生长，因为这种特殊形式的癌症过度表达MDR表型。值得注意的是，Omega-3脂肪酸-紫杉醇结合物DHA-SBT-1214可以选择性地穿透这些癌细胞，绕过MDR装置，从而诱导细胞死亡。进一步开发DHA-SBT-1214作为结肠癌、胰腺癌、肺癌、乳腺癌和其他形式的癌症的可能治疗方法，在这种多变量且基本上无法治疗的疾病的多种形式似乎正在增加的社会中，几乎没有比这更相关的了。

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.