Improving Outcomes for Multiple Myeloma Patients through Novel Therapeutic Interventions

项目总结 多发性骨髓瘤(MM)是一种无法治愈的血癌，在美国大约有83,000人受到影响。 尽管近年来多发性骨髓瘤的治疗有了显著的改善，但绝大多数患者都经历了 多次复发，最终死于该病的并发症。在过去的12年里，我，研究 都致力于为改善癌症患者的预后做出贡献。自2014年以来，我 我在单位主任弗拉维亚·皮奇奥里的实验室工作，在那里我们专门研究MM。我现在 参与了三项由国家癌症研究所资助的研究。1)放射免疫疗法/CAR T细胞：用途 治疗性同位素，如贝塔发射体177Lu或阿尔法发射体225Ac增加了特异性杀伤力 对癌细胞的影响，但副作用是临床关注的问题。尽管CAR T细胞可能会减轻肿瘤负担，但患者 仍然有复发的风险。我们预测CD38导向的放射免疫疗法和CS1导向的CAR的使用 T细胞将导致更持久的缓解，同时降低每种药物的剂量，并减少副作用 和增强的免疫调节。2)溶血素：溶血素是一种肿瘤病毒，在多发性骨髓瘤中仅表现出适度的活性 患者，可能是因为对肿瘤病毒的耐药机制。我们观察到carflizomib，一秒钟 产生蛋白酶体抑制剂，与溶血素联合在体外显示出协同杀伤MM细胞的作用。我们 发现卡菲佐米通过调节细胞的抗病毒反应来促进溶血素感染 微环境。我们还发现，HDAC抑制剂可以减少一种重要的表面表达 黏附受体和上调肿瘤病毒受体的表达。3)攻克IMID研究 骨髓瘤：为了克服对来那度胺(LEN)等免疫调节药物(IMids)的抗药性， 联合治疗可能是必要的。我研究了安全的口服药物来氟米特(Lef)， 在过去的20年里，它一直用于治疗类风湿性关节炎。我们证明了LEF直接抑制了 几种激酶，包括MM细胞中的PIM丝氨酸/苏氨酸激酶家族，对c-Myc产生负面影响 蛋白质水平，通常在MM中上调。根据这些信息，我们推断一种合适的药物 联合使用的是免疫调节药物来那度胺(LEN)。项目目标的完成 在很大程度上取决于我的资历，到目前为止的结果表明，我作为一名研究专家在 癌症研究界。

PROJECT SUMMARY Multiple myeloma (MM) is an incurable blood cancer affecting approximately 83,000 people in the United States. Although treatments for MM have improved significantly in recent years, the vast majority of patients experience multiple relapses and ultimately succumb to complications of the disease. For the last 12 years, I, the Research Specialist, have devoted my work toward contributing to improving outcomes for cancer patients. Since 2014, I have worked in the laboratory of Unit Director Flavia Pichiorri, where we exclusively specialize in MM. I am now involved with three National Cancer Institute–funded studies. 1) Radioimmunotherapy/CAR T cells: The use of therapeutic isotopes such as the beta emitter 177Lu or the alpha emitter 225Ac have increased the specific killing of cancer cells, but side effects are clinical concerns. Although CAR T cells may reduce tumor burden, patients remain at risk of relapse. We predict that the use of CD38-directed radioimmunotherapy and CS1-directed CAR T cells will result in more durable remissions while lowering the dose for each agent, with decreased side effects and enhanced immunomodulation. 2) Reolysin: Reolysin, an oncovirus, shows only modest activity in MM patients, likely because of resistance mechanisms to oncoviruses. We observed that carflizomib, a second generation proteasome inhibitor, showed synergic killing of MM cells in vitro when combined with Reolysin. We found that carfilzomib facilitates Reolysin infection through modulation of the antiviral response of the microenvironment. We also discovered that HDAC inhibitors can reduce the surface expression of an important adhesion receptor and upregulate the expression of an oncovirus receptor. 3) Overcoming IMiD research in myeloma: To overcome disease resistance to immunomodulatory drugs (IMiDs) such as lenalidomide (Len), combinatorial therapies may be necessary. I have investigated the safe, orally available drug leflunomide (Lef), which has been used for rheumatoid arthritis for the last 20 years. We demonstrated that Lef directly inhibits several kinases, including the PIM family of serine/threonine kinases in MM cells, negatively affecting c-Myc protein levels, which are commonly upregulated in MM. With this information, we reasoned that a suitable drug to use in combination is the immunomodulatory drug lenalidomide (Len). The completion of the projects’ goals will rely in large part on my qualifications, and the results thus far point to my value as a Research Specialist in the cancer research community.