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KRAS, NRAS and BRAF mutations are among the most important oncogenic drivers in many major cancer types, such as melanoma, lung, colorectal and pancreatic cancer. There is currently no effective therapy for the treatment of RAS mutant cancers. LY3009120, a pan-RAF and RAF dimer inhibitor advanced to clinical study has been shown to inhibit both RAS and BRAF mutant cell proliferation in vitro and xenograft tumor growth in vivo. Abemaciclib, a CDK4/6-selective inhibitor, is currently in phase III studies for ER-positive breast cancer and KRAS mutant lung cancer. In this study, we found that combinatory treatment with LY3009120 and abemaciclib synergistically inhibited proliferation of tumor cells in vitro and led to tumor growth regression in xenograft models with a KRAS, NRAS or BRAF mutation at the doses of two drugs that were well tolerated in combination. Further in vitro screen in 328 tumor cell lines revealed that tumor cells with KRAS, NRAS or BRAF mutation, or cyclin D activation are more sensitive, whereas tumor cells with PTEN, PIK3CA, PIK3R1 or retinoblastoma (Rb) mutation are more resistant to this combination treatment. Molecular analysis revealed that abemaciclib alone inhibited Rb phosphorylation partially and caused an increase of cyclin D1. The combinatory treatment cooperatively demonstrated more complete inhibition of Rb phosphorylation, and LY3009120 suppressed the cyclin D1 upregulation mediated by abemaciclib. These results were further verified by CDK4/6 siRNA knockdown. Importantly, the more complete phospho-Rb inhibition and cyclin D1 suppression by LY3009120 and abemaciclib combination led to more significant cell cycle G 0 /G 1 arrest of tumor cells. These preclinical findings suggest that combined inhibition of RAF and d-cyclin-dependent kinases might provide an effective approach to treat patients with tumors harboring mutations in RAS or RAF genes.

The methodology of blood sample preparation and analysis has been examined to further evaluate the technique of electron spin resonance (ESR) for possible use in detecting cancer and in monitoring the progress of cancer therapy. Frozen whole blood and serum samples from 278 normal donors and 97 cancer patients were studied by ESR for signal intensity from Cu+2 bound to ceruloplasmin (g factor = 2.05). The signal from this species (Cu+2-CP) in serum rose sharply during the first two hours of storage at room temperature after being drawn from the subject, and then reached a plateau. The average Cu+2-CP ESR signal intensity was significantly different for control groups of males, females not taking estrogen medication, and females taking estrogens. The mean ESR signal intensities of Cu+2-CP from cancer patients separated into the same groups as the control data were approximately twice as great as the mean control levels. Total serum copper levels were correlated with ESR intensities of Cu+2-CP and indicated that the ratio of Cu+2/Cu+1 in CP is higher in serum from cancer patients than from controls.

Two hundred episodes of fungemia that occurred at Memorial Sloan-Kettering Cancer Center between January 1, 1978, and June 30, 1982, are reviewed and compared with those seen from 1974 through 1977. The total number of episodes of fungemia per year increased by 30.6%, episodes per 100 new lymphoma and solid tumor patients increased by 73% and 95%, respectively, and episodes per 100 new leukemia patients decreased by 50%. Fungemia also occurred earlier during hospitalization, and embolic skin lesions were a common early sign of Candida tropicalis fungemia. Mortality was not significantly different with and without amphotericin B therapy in fungemic patients with leukemia, lymphoma, or aplastic anemia (51 of 70 vs. 21 of 24) or solid tumors (29 of 36 vs. 29 of 43); however, some patients appeared to benefit from combination therapy with amphotericin B and flucytosine. The prevalence of disseminated candidiasis at autopsy was the same in treated (11 of 15) and untreated (8 of 11) patients with leukemia, lymphoma, and aplastic anemia, but it was significantly lower in treated (none of 8) than in untreated (5 of 11) patients with solid tumors.