Therapeutic enzyme depletion of L-serine for cancer treatment

L-丝氨酸的治疗性酶消耗用于癌症治疗

• 批准号: 10650618
• 负责人: Jonathan L. Coloff
• 金额: $ 65万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10650618
• 关键词: Acute Lymphocytic Leukemia; Amino Acids; Anabolism; Asparagine; Biodistribution; Cancer Patient; Chemistry; Circulation; Clinical; Consumption; Data; Development; Diet; Diet Modification; Disease; Engineering; Enzymes; Estrogen receptor positive; Goals; Growth; Human; Human Engineering; Hydro-Lyases; Immune; Immune system; Malignant Neoplasms; Mammary Neoplasms; Mediating; Metabolism; Methods; Modality; Modeling; Mus; Mutation; Myeloid-derived suppressor cells; Neurologic; Nutrient; Outcome; Pathway interactions; Patients; Pegaspargase; Pharmacodynamics; Physiological; Positioning Attribute; Pre-Clinical Model; Property; Protein Engineering; Proteins; Role; Route; Serine; Serum; Starvation; Structure; Synthetic Diet; T-Lymphocyte; Testing; Therapeutic; Therapeutic Agents; Treatment Efficacy; Tumor Immunity; Tumor-associated macrophages; addiction; asparaginase; auxotrophy; cancer cell; cancer therapy; cell type; clinical development; compliance behavior; cytokine; deprivation; dietary; effective therapy; efficacy evaluation; experimental study; extracellular; high throughput screening; improved; in vivo; interest; malignant breast neoplasm; mouse model; novel therapeutics; pharmacologic; prototype; side effect; standard of care; success; synergism; targeted treatment; therapeutic enzyme; therapeutically effective; tumor; tumor growth; tumor metabolism

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.

项目总结 丝氨酸是肿瘤生长所必需的营养物质，让癌细胞挨饿引起了人们的极大兴趣。 用于癌症治疗的丝氨酸。例如，我们最近发现腔/ER+乳腺肿瘤，它 占所有乳腺癌死亡人数的大约一半，不能合成丝氨酸(即，他们 丝氨酸营养缺乏症)，因此特别容易受到丝氨酸缺乏的影响。膳食丝氨酸 饥饿是目前降低体内丝氨酸利用率的唯一方法，但这种方法将很难 在人类身上实施，因为它需要极端的饮食改变。此外，膳食丝氨酸 饥饿只能将循环中的丝氨酸水平降低50%，这可能不足以抑制 很多肿瘤。治疗性酶是体内控制营养水平的另一种方法， 已被证明是治疗癌症和其他疾病的有效方法。我们假设一种治疗方法 丝氨酸降解酶可能是实现体内丝氨酸饥饿治疗癌症的更有效的方法 心理治疗。为了验证这一假设，我们开发了一种新型的治疗性丝氨酸降解酶， 人丝氨酸脱水酶(ESDH)，能够将循环中的丝氨酸水平降低90%以上 老鼠不需要任何饮食上的改变。我们的初步数据显示，丝氨酸的长期消耗 ESDH具有良好的小鼠耐受性，并能够在多种小鼠模型中抑制肿瘤生长。这个 这项提议的首要目标是优化eSDH以产生一种适合于 随后的临床发展，并在临床前模型中评估其作为一种潜在的癌症治疗方法。至 为了实现这些目标，我们提出的实验将1)设计一种更具选择性和稳定性的优化eSDH 具有增强药理特性的酶2)评估生理影响和潜在的副作用- 酶促丝氨酸耗竭的影响，3)评估eSDH对营养缺陷型肿瘤的疗效 丝氨酸，以及4)进一步研究我们的初步发现，eSDH治疗诱导抗肿瘤免疫。一个 丝氨酸缺乏性肿瘤的靶向治疗方法也可以诱导抗肿瘤免疫 为腔内乳腺癌和其他恶性肿瘤患者提供一种有效的治疗方式。