作者: Khan, Zakir ; Tourtellotte, Warren G ; Nishi, Erika ; Cao, DuoYao ; Bernstein, Ellen A ; Zhao, Tuantuan V ; Yamashita, Michifumi ; Bernstein, Kenneth E ; Saito, Suguru ; Shibata, Tomohiro

As part of the classical renin-angiotensin system, the peptidase angiotensin-converting enzyme (ACE) makes angiotensin II which has myriad effects on systemic cardiovascular function, inflammation, and cellular proliferation. Less well known is that macrophages and neutrophils make ACE in response to immune activation which has marked effects on myeloid cell function independent of angiotensin II. Here, we discuss both classical (angiotensin) and nonclassical functions of ACE and highlight mice called ACE 10/10 in which genetic manipulation increases ACE expression by macrophages and makes these mice much more resistant to models of tumors, infection, atherosclerosis, and Alzheimer's disease. In another model called NeuACE mice, neutrophils make increased ACE and these mice are much more resistant to infection. In contrast, ACE inhibitors reduce neutrophil killing of bacteria in mice and humans. Increased expression of ACE induces a marked increase in macrophage oxidative metabolism, particularly mitochondrial oxidation of lipids, secondary to increased peroxisome proliferator-activated receptor α expression, and results in increased myeloid cell ATP. ACE present in sperm has a similar metabolic effect, and the lack of ACE activity in these cells reduces both sperm motility and fertilization capacity. These nonclassical effects of ACE are not due to the actions of angiotensin II but to an unknown molecule, probably a peptide, that triggers a profound change in myeloid cell metabolism and function. Purifying and characterizing this peptide could offer a new treatment for several diseases and prove potentially lucrative.

2024-05-01·Targeted Oncology

A Phase I Trial Evaluating the Addition of Lenalidomide to Patients with Relapsed/Refractory Multiple Myeloma Progressing on Ruxolitinib and Methylprednisolone

Article

作者: Safaie, Tahmineh ; Eshaghian, Shahrooz ; Eades, Benjamin M ; Moezi, Mehdi ; Del Dosso, Ashley ; Limon, Andrea ; Vescio, Robert ; Yang, Honghao ; Berenson, James R ; Ray, Rudra ; Bujarski, Sean ; Brobeck, Matthew ; Rice, Stephanie ; Lim, Stephen ; Boccia, Ralph ; Sebhat, Yohana ; Schwartz, Gary ; Swift, Regina ; Kim, Susanna

BACKGROUNDRuxolitinib (RUX), an orally administered selective Janus kinase 1/2 inhibitor, has received approval for the treatment of myelofibrosis, polycythemia vera, and graft-versus-host disease. We have previously demonstrated the anti-multiple myeloma effects of RUX alone and in combination with the immunomodulatory agent lenalidomide (LEN) and glucocorticosteroids both pre-clinically and clinically.OBJECTIVEThis study aims to evaluate whether LEN can achieve clinical activity among patients with multiple myeloma progressing on the combination of RUX and methylprednisolone (MP).METHODSIn this part of a phase I, multicenter, open-label study, we evaluated the safety and efficacy of RUX and MP for patients with multiple myeloma with progressive disease who had previously received a proteasome inhibitor, LEN, glucocorticosteroids, and at least three prior regimens; we also determined the safety and efficacy of adding LEN at the time of disease progression from the initial doublet treatment. Initially, all subjects received oral RUX 15 mg twice daily and oral MP 40 mg every other day. Those patients who developed progressive disease according to the International Myeloma Working Group criteria then received LEN 10 mg once daily on days 1-21 within a 28-day cycle in addition to RUX and MP, which were administered at the same doses these patients were receiving at the time progressive disease developed.RESULTSTwenty-nine subjects (median age 64 years; 18 [62%] male) were enrolled in this part of the study and initially received the two-drug combination of RUX and MP. The median number of prior therapies was six (range 3-12). The overall response rate from this two-drug combination was 31% and the clinical benefit rate was 34%. The best responses were 1 very good partial response, 8 partial responses, 1 minor response, 12 stable disease, and 7 progressive disease. The median progression-free survival was 3.5 months (range 0.5-36.2 months). The median time to response was 3.0 months. The median duration of response was 12.5 months (range 2.8-36.2 months). Twenty (69%) patients who showed progressive disease had LEN added to RUX and MP; all patients had prior exposure to LEN and all but one patient was refractory to their last LEN-containing regimen. After the addition of LEN, the overall response rate was 30% and the clinical benefit rate was 40%. The best responses of patients following the addition of LEN were 2 very good partial responses, 4 partial responses, 2 minor responses, 8 stable disease, and 4 progressive disease. The median time to response was 2.6 months (range 0.7-15.0 months). The median duration of response was not reached. The median progression-free survival following the addition of LEN was 3.5 months (range 0.3-25.9 months).CONCLUSIONSFor patients with multiple myeloma, treatment with RUX and MP is effective and well tolerated, and LEN can be used to extend the benefit of this RUX-based treatment.CLINICAL TRIAL REGISTRATIONThis study is registered with ClinicalTrials.gov, NCT03110822, and is ongoing.

2024-02-05·Oncotarget

Preclinical and clinical evaluation of the Janus Kinase inhibitor ruxolitinib in multiple myeloma

Article

作者: Del Dosso, Ashley ; Berenson, James R. ; Tadevosyan, Elizabeth

Multiple myeloma (MM) is the most common primary malignancy of the bone marrow. No established curative treatment is currently available for patients diagnosed with MM. In recent years, new and more effective drugs have become available for the treatment of this B-cell malignancy. These new drugs have often been evaluated together and in combination with older agents. However, even these novel combinations eventually become ineffective; and, thus, novel therapeutic approaches are necessary to help overcome resistance to these treatments. Recently, the Janus Kinase (JAK) family of tyrosine kinases, specifically JAK1 and JAK2, has been shown to have a role in the pathogenesis of MM. Preclinical studies have demonstrated a role for JAK signaling in direct and indirect growth of MM and downregulation of anti-tumor immune responses in these patients. Also, inhibition of JAK proteins enhances the anti-MM effects of other drugs used to treat MM. These findings have been confirmed in clinical studies which have further demonstrated the safety and efficacy of JAK inhibition as a means to overcome resistance to currently available anti-MM therapies. Additional studies will provide further support for this promising new therapeutic approach for treating patients with MM.

项与 Institute For Myeloma & Bone Cancer Research 相关的新闻（医药）

2023-09-19

·PRNewswire

Institute for Myeloma & Bone Cancer Research Announces Publication in Targeted Oncology

Longest Survival Reported to Date for Multiple Myeloma Patients WEST HOLLYWOOD, Calif., Sept. 19, 2023 /PRNewswire/ -- The Institute for Myeloma & Bone Cancer Research (IMBCR) announces the publication in Targeted Oncology on the outstanding survival of 161 unselected, new patients with multiple myeloma (MM) who started treatment from 2006 to 2022 at Berenson Cancer Center. In 2023, the American Cancer Society anticipates about 35,730 new cases of MM will be diagnosed (19,860 in men and 15,870 in women). Approximately 12,590 deaths are expected to occur this year (7,000 in men and 5,590 in women). This study shows an average survival of 136.2 months. It is the longest reported in any population of unselected, newly diagnosed multiple myeloma patients. Average survival was even longer (173.5 months) for those younger than 65. While myeloma care centers consider stem cell transplant as the standard first treatment, none of the patients in this clinical setting received a stem cell transplant. James R. Berenson, MD, Medical and Scientific Director of IMBCR, led this team and stated, "Round-the-clock physician access and more frequent monitoring of each patient's status allowing rapid changes in treatments that are either not working or causing unwanted side effects and access to the latest treatments have resulted in these unprecedented outcomes." This comprehensive and personalized approach by a forward-thinking myeloma expert has resulted in publication of the longest survival reported to date. About the Institute for Myeloma & Bone Cancer Research (IMBCR) Founded by Dr. James R. Berenson in 2003, IMBCR is a West Hollywood-based independent non‑profit cancer research institute dedicated to discovering and developing more effective treatments, and ultimately a cure for myeloma and bone cancer. IMBCR's innovative research provides cancer patients with greater longevity and an improved quality of life. The Institute's multiple myeloma related research is far-reaching and benefits all cancers where bone metastasis is a threat. This includes those with breast cancer, lung cancer, and prostate cancer as well as other types of bone marrow and blood cancer such as lymphoma and leukemia. Because of expanded drug therapy options and treatment combinations, IMBCR provides patients with an opportunity to enhance their chances of surviving cancer and conquer one of the hardest challenges of their lives. These results provide patients, caregivers, and healthcare professionals with a much more optimistic outlook for those dealing with this B-cell malignancy. About Berenson Cancer Center (BCC) Berenson Cancer Center is a comprehensive clinic that has specialized in the treatment of patients with multiple myeloma and related diseases for more than 20 years. James R. Berenson, MD, President and Medical Director, has been conducting clinical and basic research for over 40 years. He has published nearly 300 peer-reviewed articles. Dr. Berenson has been involved in many of the major breakthroughs that have brought new treatments to patients with these diseases resulting in both an improvement in the length and quality of their lives. About Multiple Myeloma Multiple myeloma is a cancer of plasma cells. Normal plasma cells are found in the bone marrow and are an important part of the immune system. The immune system is made up of several types of cells that work together to fight infections and other diseases. Lymphocytes (lymph cells) are one of the main types of white blood cells in the immune system and include T cells and B cells. Lymphocytes are in many areas of the body, such as lymph nodes, bone marrow, intestines, and bloodstream. Contact: Jessica Yataco, MBA Chief Operations Officer Institute for Myeloma & Bone Cancer Research [email protected] Media Contact Susan Heins 864-346-8336 [email protected] SOURCE Institute for Myeloma & Bone Cancer Research

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