An inhibitor of oxidative phosphorylation exploits cancer vulnerability.

Metabolic reprograming is an emerging hallmark of tumor biology and an actively pursued opportunity in discovery of oncology drugs. Extensive efforts have focused on therapeutic targeting of glycolysis, whereas drugging mitochondrial oxidative phosphorylation (OXPHOS) has remained largely unexplored, partly owing to an incomplete understanding of tumor contexts in which OXPHOS is essential. Here, we report the discovery of IACS-010759, a clinical-grade small-molecule inhibitor of complex I of the mitochondrial electron transport chain. Treatment with IACS-010759 robustly inhibited proliferation and induced apoptosis in models of brain cancer and acute myeloid leukemia (AML) reliant on OXPHOS, likely owing to a combination of energy depletion and reduced aspartate production that leads to impaired nucleotide biosynthesis. In models of brain cancer and AML, tumor growth was potently inhibited in vivo following IACS-010759 treatment at well-tolerated doses. IACS-010759 is currently being evaluated in phase 1 clinical trials in relapsed/refractory AML and solid tumors

Unusual Case of Anaplastic Large Cell Lymphoma Presenting as a Breast Mass in a Patient with no History of Breast Implants

Adenocarcinoma is the most common malignant neoplasm involving breast tissue. In contrast to carcinomas, the other types of malignant neoplasms involving the breast are relatively uncommon. One of the examples of this rare entity is lymphoma. Traditionally, non-Hodgkin lymphomas (NHL) involving the breast are divided into primary lymphoma of the breast and systemic lymphoma, although the distinction could be challenging. Most of NHL involving breast tissue have B cell origin; T cell NHL represents less than 20% of all lymphoma cases. Anaplastic large cell lymphomas (ALCL) involving the breast accounts for even lower percentage of cases. Similar to ALCL involving other sites, there are several main types of ALCL identified: primary cutaneous ALCL and systemic ALCL, which is subdivided into ALK positive and ALK negative subtypes. Relatively recently, an additional distinct subtype of ALK-negative ALCL was described, which is associated with textured breast implants and needs to be considered as a differential diagnosis if patient has a history of breast implants. Here, we report a case of ALCL presented as a breast mass without history of breast implant and discuss similar cases published in the literature

Usefulness of CD11a and CD18 in flow cytometric immunophenotypic analysis for diagnosis of acute promyelocytic leukemia

Acute promyelocytic leukemia (APL) is an aggressive disease that requires prompt diagnosis and therapy. Flow cytometry immunophenotyping can serve as a screening test for APL before the results of cytogenetic or molecular testing for t(15;17)(q22;q21)/PML-RARα are often dimly expressed or absent in APL. We used flow cytometry immunophenotyping with an antibody panel including CD11a and CD18 to assess 36 APL and 33 other AML cases. HLA-DR, CD11a, and CD18 were absent in 81% of APL and 12% of other AML cases (specificity, 88%). By further including combinations of HLA-DR-, CD2+, and either CD11a- or CD18-, we identified 92% of APL cases with 85% specificity. These data compare favorably with the combination of HLA-DR-, CD34-, and CD117+ for APL diagnosis, which had a sensitivity of 64% in this study