PubMed · 9171069
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R Bataille, J L Harousseau. 1997-06-05. Multiple myeloma.. https://doi.org/10.1056/nejm199706053362307
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Drug response differs substantially in cancer patients due to inter- and intra-tumor heterogeneity. Particularly, transcriptome context, especially tumor microenvironment, has been shown playing a significant role in shaping the actual treatment outcome. In this study, we develop a deep variational autoencoder (VAE) model to compress thousands of genes into latent vectors in a low-dimensional space. We then demonstrate that these encoded vectors could accurately impute drug response, outperform standard signature-gene based approaches, and appropriately control the overfitting problem. We apply rigorous quality assessment and validation, including assessing the impact of cell line lineage, cross-validation, cross-panel evaluation, and application in independent clinical data sets, to warrant the accuracy of the imputed drug response in both cell lines and cancer samples. Specifically, the expression-regulated component (EReX) of the observed drug response achieves high correlation across panels. Using the well-trained models, we impute drug response of The Cancer Genome Atlas data and investigate the features and signatures associated with the imputed drug response, including cell line origins, somatic mutations and tumor mutation burdens, tumor microenvironment, and confounding factors. In summary, our deep learning method and the results are useful for the study of signatures and markers of drug response.
Nonradiomimetic drugs, hydroxyurea (HU) and pipobroman (Pi), were administred to relatively young subjects with polycythemia vera (PV) in an attempt to decrease the leukemogenic risk observed in patients treated with 32P. Clinical safety, hematological efficacy, risk of carcinoma or leukemia, and frequency of progression to myelofibrosis have not yet been defined in long-term studies, and no comparative studies of HU and Pi have been conducted. Since 1980, 292 patients with PV diagnosed before the age of 65 years were randomized to receive treatment with HU (25 mg/kg/d, followed by low-dose maintenance) or Pi (1.2 mg/kg/d, followed by low-dose maintenance). Patients were followed until death or until May 1997. Drug tolerance was often poor; leg ulcers and buccal aphthous ulcers (with HU) and gastric pain and diarrhea (with Pi) sometimes required treatment change, mainly in the HU arm. Hematological stability, especially in terms of platelet count, was very often insufficient with HU (45% of cases), but the risk of thrombo-embolic event was similar in both arms. Actuarial survival was similar in the two arms and shorter than that of the reference population. The risk of leukemia was approximately 10% at the 13th year, with no significant difference between the two arms. The risk of carcinoma (when excluding the skin cancers) was similar in both groups. There was a high risk of progression to myelofibrosis in the patients treated by HU, which was significantly higher than with Pi.
Protein kinase C (PKC) isozymes play distinct roles in cellular function. In human K562 leukemia cells, PKC alpha is important for cellular differentiation and PKC betaII is required for proliferation. In this report, we assess the role of the atypical PKC isoform PKC iota in K562 leukemia cell physiology. K562 cells were stably transfected with expression plasmids containing the cDNA for human PKC iota in sense or antisense orientation to increase or decrease cellular PKC iota levels, respectively. Overexpression or inhibition of expression of PKC iota had no significant effect on the proliferative capacity of K562 cells nor their sensitivity to phorbol myristate acetate-induced cytostasis and megakaryocytic differentiation, suggesting that PKC iota does not play a critical role in these processes. Rather, PKC iota serves to protect K562 cells against drug-induced apoptosis. K562 cells, which are resistant to most apoptotic agents, undergo apoptosis when treated with the protein phosphatase inhibitor okadaic acid (OA). Overexpression of PKC iota leads to increased resistance to OA-induced apoptosis whereas inhibition of PKC iota expression sensitizes cells to OA-induced apoptosis. Overexpression of the related atypical PKC zeta has no protective effect, demonstrating that the effect is isotype-specific. PKC iota also protects K562 cells against taxol-induced apoptosis, indicating that it plays a general protective role against apoptotic stimuli. These data support a role for PKC iota in leukemia cell survival.