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.

项目概要 丝氨酸是肿瘤生长的必需营养素，人们对饥饿癌细胞非常感兴趣 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人数的一半，无法从头合成丝氨酸（即，它们 丝氨酸营养缺陷型），因此特别容易受到丝氨酸缺乏的影响。膳食丝氨酸 饥饿是目前减少体内丝氨酸可用性的唯一方法，但这种方法很难 由于它需要极端的饮食改变，因此在人类中实施。此外，膳食丝氨酸 饥饿只能使循环丝氨酸水平降低 50%，这可能不足以抑制丝氨酸的生长 许多肿瘤。治疗性酶是控制体内营养水平的另一种方法， 已被证明可以有效治疗癌症和其他疾病。我们假设一种治疗方法 丝氨酸降解酶可能是实现癌症体内丝氨酸饥饿的更有效方法 治疗。为了检验这一假设，我们开发了一种新型治疗性丝氨酸降解酶，经过改造 人丝氨酸脱水酶 (eSDH)，能够将循环丝氨酸水平降低 90% 以上 小鼠不需要任何饮食改变。我们的初步数据表明，长期丝氨酸耗竭 eSDH 对小鼠具有良好的耐受性，并且能够在多种小鼠模型中抑制肿瘤生长。这 该提案的总体目标是优化 eSDH 以生成适合的酶 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方法。到 为了实现这些目标，我们提出的实验将 1) 设计出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副作用 酶促丝氨酸消耗的影响，3) 评估 eSDH 对营养缺陷型肿瘤的功效 丝氨酸，4) 进一步研究我们的初步发现，即 eSDH 治疗可诱导抗肿瘤免疫。一个 针对丝氨酸营养缺陷型肿瘤的靶向治疗方法还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有效的治疗方式。