Preclinical toxicological evaluation of HTL-001, a novel cancer therapeutic agent targeting HOX genes

同源盒或“HOX”基因是一个重要的基因家族，编码HOX蛋白，控制胚胎细胞和组织的生长。出生后，这些基因通常是沉默的，然而，它们可以在肿瘤中重新激活，它们在促进癌细胞增殖和存活方面发挥作用。重要的是，在癌症中，这些基因没有突变，而是过度表达或“开启”，并通过与其他蛋白质合作来驱动癌症增殖。我们的新药是一种小肽，可以阻止HOX蛋白与其关键伴侣蛋白PBX结合，从而导致癌细胞快速死亡。我们的药物HTL-001已经在代表14种不同恶性肿瘤的癌细胞、“试管”中的人类癌症组织以及动物中进行了测试。它一直显示出对癌细胞的选择性毒性，而不影响正常细胞/组织。一项增加一次给大鼠和兔子注射HTL-001剂量的研究已经证明HTL-001是安全无毒的。这里提出的第二项研究将在动物身上测试多剂量HTL-001的安全性，因为这与该药物在人体临床试验中的使用方式一致。如果成功，这是一个重要的科学和强制性监管步骤，将使我们能够确定HTL-001的人体试验起始剂量，该试验可能于2018年12月开始。由于目前对晚期疾病的治疗主要是姑息性的，因此迫切需要具有新的作用机制的新的癌症治疗方法。我们已经证明，HOX基因失调在大多数癌症中非常普遍，也是新疗法的合理目标。我们最近的研究表明，在植入神经胶质瘤（脑癌）的小鼠中，html -001的存活率提高了一倍。这一进展非常有希望，其结果至少与目前阶段测试的其他药物一样好，特别是我们乐观地认为html -001将具有良好的耐受性。虽然不像许多癌症那样常见，但在英国每年约有11500名患者被诊断患有脑癌，其中只有40%的患者在一年后存活下来。这是一种非常高的未满足医疗需求的情况，该项目将确保我们的药物在临床试验中对患者是安全的，有可能对患者产生重大益处-最初用于脑癌，希望长期用于其他癌症。

Homeobox or 'HOX' genes are an important family of genes encoding HOX proteins that control cell and tissue growth in the embryo. After birth, these genes are normally silenced, however, they can be re-activated in tumours in which they have a role in promoting cancer cell proliferation and survival. Importantly, in cancer, these genes are not mutated but overexpressed or 'switched on' and act through partnership with other proteins to drive cancer proliferation. Our novel drug is a small peptide which stops HOX proteins binding to their key partner protein, PBX, resulting in rapid cancer cell death. Our agent, HTL-001, has been tested in cancer cells representative of 14 different malignancies, in human cancer tissue in the 'test tube' as well as in animals. It has consistently demonstrated selective toxicity for cancer ells, sparing normal cells/tissue. A study of increasing doses of HTL-001 given once to rats and rabbits has already demonstrated that HTL-001 is safe and not toxic. The second study proposed here will test the safety of multiple doses of HTL-001 in animals since this is in line with how the drug would be used in human clinical trials. If successful, this is a vital scientific and compulsory regulatory step would allow us to define the starting dose of HTL-001 for human trials which could commence in December 2018\. There is an urgent unmet need for new cancer therapies with novel mechanisms of action as current treatments for advanced disease are largely palliative. We have shown HOX gene dysregulation is very common in most cancers, and a rational target for new treatments.We have recently shown that HTL-001 doubles the survival in mice which have been seeded with glioma (brain cancer). This development is very promising and the results are at least as good if not significantly better than other drugs tested at this stage - particulary as we are optimistic that HTL-001 will be well tolerated. Although not as common as many cancers, around 11,500 patients are diagnosed with brain cancer in the UK very year, of which only about 40% survive after one year. It is a condition of very high unmet medical need and this project, which will ensure that our drug is safe for patients' use in a clinical trial, has the potential to be of major benefit to patients - in brain cancer initially and hopefully in other cancers in the longer term.