Improving Outcomes for Multiple Myeloma Patients through Novel Therapeutic Interventions

项目摘要 多发性骨髓瘤（MM）是一种无法治愈的血液癌症，在美国影响约83，000人。 尽管近年来MM的治疗有了显著改善，但绝大多数患者经历了 多次复发并最终死于疾病的并发症。在过去的12年里，我，研究 我的工作是致力于改善癌症患者的预后。自2014年以来，我 我曾在单位主任Flavia Pichiorri的实验室工作，在那里我们专门研究MM。 参与了三项国家癌症研究所资助的研究。1)放射免疫疗法/CAR T细胞：应用 治疗性同位素如β发射体177 Lu或α发射体225 Ac增加了特异性杀伤 但副作用是临床问题。虽然CAR T细胞可以减少肿瘤负荷，但患者 仍然有复发的风险。我们预测使用CD 38导向的放射免疫治疗和CS 1导向的CAR治疗， T细胞将导致更持久的缓解，同时降低每种药物的剂量，减少副作用 和增强的免疫调节。2)Reolysin：Reolysin是一种肿瘤病毒，在MM中仅显示出中等活性 患者，可能是因为对肿瘤病毒的耐药机制。我们观察到， 第二代蛋白酶体抑制剂与Reolysin联用时，在体外显示协同杀伤MM细胞。我们 发现卡非佐米通过调节细胞的抗病毒反应促进Reolysin感染， 微环境我们还发现，HDAC抑制剂可以减少一种重要的细胞表面表达， 粘附受体并上调肿瘤病毒受体的表达。3)克服IMiD研究 骨髓瘤：为了克服对免疫调节药物（IMiD）如来那度胺（Len）的耐药性， 可能需要联合治疗。我研究了安全的口服药物来氟米特（Lef）， 在过去的20年里一直用于治疗类风湿性关节炎。我们证明了莱夫直接抑制了 几种激酶，包括MM细胞中丝氨酸/苏氨酸激酶的PIM家族，对c-Myc产生负面影响 蛋白质水平，这是通常上调MM。有了这个信息，我们推断，一个合适的药物， 联合使用的是免疫调节药物来那度胺（Len）。完成项目目标 在很大程度上取决于我的资格，到目前为止的结果表明我作为一名研究专家的价值， 癌症研究团体。

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.