Therapeutic enzyme depletion of L-serine for cancer treatment

项目摘要 丝氨酸是肿瘤生长的必需营养素，并且存在使癌细胞饥饿的显著兴趣。 丝氨酸用于癌症治疗。例如，我们最近发现，管腔/ER+乳腺肿瘤， 约占所有乳腺癌死亡的一半，不能从头合成丝氨酸（即，他们 是丝氨酸营养缺陷型的），因此特别易受丝氨酸剥夺的影响。膳食丝氨酸 饥饿是目前降低体内丝氨酸可用性的唯一方法，但这种方法将难以 在人类中实施，因为它需要极端的饮食调整。此外，膳食丝氨酸 饥饿只能使循环丝氨酸水平降低50%，这可能不足以抑制生长。 许多肿瘤。治疗酶是一种在体内操纵营养水平的替代方法， 已被证明是治疗癌症和其他疾病的有效方法。我们假设一种治疗药物 丝氨酸降解酶可能是一种更有效的体内丝氨酸饥饿治疗癌症的方法 疗法为了验证这一假设，我们开发了一种新的治疗性丝氨酸降解酶， 人丝氨酸脱氢酶（eSDH），其能够使循环丝氨酸水平降低大于90%， 不需要任何饮食改变的小鼠。我们的初步数据表明， 小鼠耐受性良好，并且能够在多种小鼠模型中抑制肿瘤生长。的 该提案的首要目标是优化eSDH以产生适合于以下的酶： 随后的临床开发，并在临床前模型中评估其作为潜在的癌症治疗剂。到 为了实现这些目标，我们提出了实验，将1）工程师更有选择性和稳定的优化eSDH 具有增强的药理学特性的酶2）评估生理影响和潜在副作用- 3）评估eSDH针对丝氨酸营养缺陷型肿瘤的功效， 丝氨酸，和4）进一步研究我们的初步发现，eSDH治疗诱导抗肿瘤免疫。一 丝氨酸营养缺陷型肿瘤的靶向治疗方法也可诱导抗肿瘤免疫， 为患有腔型乳腺癌和其他恶性肿瘤的患者提供有效的治疗方式。

PROJECT SUMMARY Serine is an essential nutrient for tumor growth, and there is significant interest in starving cancer cells of serine for cancer therapy. For example, we have recently found that luminal/ER+ breast tumors, which account for approximately half of all breast cancer fatalities, are unable synthesize serine de novo (i.e., they are auxotrophic for serine) and are therefore particularly vulnerable to serine deprivation. Dietary serine starvation is currently the only method of reducing serine availability in vivo, but this approach will be difficult to implement in humans due to the extreme dietary modifications it requires. Furthermore, dietary serine starvation can only reduce circulating serine levels by 50%, which may not be sufficient to inhibit the growth of many tumors. Therapeutic enzymes are an alternative method of manipulating nutrient levels in vivo that have proven to be effective treatments for cancer and other diseases. We hypothesized that a therapeutic serine degrading enzyme might be a more effective method of achieving in vivo serine starvation for cancer therapy. To test this hypothesis, we have developed a novel therapeutic serine degrading enzyme, engineered human serine dehydratase (eSDH), that is capable of reducing circulating serine levels by greater than 90% in mice without the need for any dietary changes. Our preliminary data suggests that prolonged serine depletion with eSDH is well-tolerated by mice and capable of inhibiting tumor growth in multiple mouse models. The overarching goals of this proposal are to optimize eSDH to generate an enzyme that is suitable for subsequent clinical development and to evaluate it as a potential cancer therapeutic in pre-clinical models. To achieve these goals, we propose experiments that will 1) engineer a more selective and stable optimized eSDH enzyme with enhanced pharmacological properties 2) assess the physiological impact and potential side- effects of enzymatic serine depletion, 3) evaluate the efficacy of eSDH against tumors that are auxotrophic for serine, and 4) further investigate our preliminary finding that eSDH treatment induces anti-tumor immunity. A targeted therapeutic approach for serine auxotrophic tumors that also induces anti-tumor immunity could provide an effective treatment modality for patients with luminal breast cancer and other malignancies.