It is now generally recognized that genomic sequence alterations are not required for establishing induced pluripotent stem cells (iPS cells), while epigenetic modifications, as exemplified by DNA methylation, undergo dynamic changes. We have been attempting application of iPS cell technology to cancer research by using it as a tool for actively modifying the epigenomic state. This presentation briefly reviews the ongoing activities intended to reprogram cancer cells, and deals with the characteristic features of the reprogrammed cancer cells. Furthermore, we shall present a cancer cell-derived iPS cell redifferentiation model and discuss the association between the genomic sequence abnormality and epigenetic regulations related to cellular differentiation. Finally, we shall introduce a tumorigenesis model based on cellular reprogramming in vivo, and discuss the relation of acquisition of stemness to the development of blastomas. We would like to introduce epigenetic regulation in cancer cells, which has been uncovered by utilizing the iPS cell technology.

Preemptive medicine will be realized through providing decision support in real time by using inference based on individualized life course data. The devices constituting such a system are termed ambient electronics. With the recent advances in Micro Electro Mechanical Systems (MEMS) technologies, ultra-small sensors have been developed, making it easier to acquire life course data via the use of ambient electronic devices with built-in ultra-small sensors. In order to develop methods for life course data analysis, on the other hand, it is imperative to alter the conventional framework of life science involving inference from genetic factors and environmental factors into a framework which enables representation of changes via the concept of state and context. With this framework, it will become feasible to carry out predictive analysis of vital phenomena through application of deep learning and artificial intelligence technologies, e.g., Bayesian estimation, a field in which remarkable progress has been made in recent years.
Reference: Chapter 3. Section 6. Realization of preemptive medicine by data-driven research. In: Experimental Medicine (Jikken-Igaku), Vol. 33-No. 7, 176-183, April 2015.

Phenylbutyrate (PB) is currently prescribed for patients with hyperammonaemia due to urea cycle disorders and its safety in pediatric patients has been established. Basic laboratory studies have demonstrated that PB is endowed with a Histone Deacetylase (HDAC)-inhibitory effect and has antineoplastic activity. Efficacy of PB in patients with tumors such as brain tumor, melanoma, leukemia, cancer of the colon and cancer of the prostate has been reported. However, at present, administration of PB to cancer patients is not covered by the national health insurance system in Japan. Our study group has previously reported our clinical experience with the use of PB in cancer patients, which includes reports of cases where the drug was effective. This study was undertaken to investigate the sensitivity to PB of cancer cells and explore the molecular mechanisms underlying such sensitivity. Among breast cancer cell lines, PB-sensitive cell lines and PB-resistant cell lines were identified and subjected to comprehensive gene expression analysis using microarrays. The analysis revealed that the candidate resistance genes (ANKD1, Ets1, KIAA1199, IFI16, and PTRF/cavin-1) and candidate sensitivity genes (Rab25 and ESRP1) were under epigenetic control. Experiments employing gene transfer disclosed involvement of the Rab25 and ESRP1 genes in the sensitivity to PB, and their upstream gene (Zeb1) was identified. Zeb1 was noted to be further controlled epigenetically by MiR200 and others. A study on Zeb1 expression and drug sensitivity in breast cancer has been initiated.

In this report, we describe a case encountered recently by us, in which a gratifying response to phenylbutyrate therapy was achieved.
[Case] A 64-year-old woman with cancer of the ovary
[Course] The patient was treated by simple total hysterectomy combined with bilateral adnexectomy and pelvic lymphadenectomy for the diagnosis of cancer of the ovary on October 29, 2009. Histopathologically, the lesion was diagnosed as a mixed-type (transitional cell carcinoma and endometrioid adenocarcinoma), poorly differentiated T1aN0M0 tumor, without evidence of extramural invasion. Therefore, the patient was administered three cycles of PTX + CDDP chemotherapy as postoperative adjuvant treatment from November 2009.
A CT performed in October 2010 revealed metastasis to the left internal iliac lymph nodes, and the patient was given chemotherapy with such regimens as DTX + CPT-11, GEM alone, and ADM alone from October 2010 to June 2013. However, multiple hepatic metastases, hydronephrosis due to the intrapelvic lesions, and invasion into the rectum (sigmoid colon) were noted on the repeat computed tomography (CT) performed in June 2013. Therefore, standard treatments were concluded as being ineffective in this case, and palliative treatment was scheduled.
In July 2013, the patient was started on oral phenylbutyrate at the dose of 6 g/day. At first, the patient was unable to even take an oral dose or could barely take a 1-g dose daily, because of pronounced abdominal symptoms such as anorexia, abdominal pain and melena. She also had repeated episodes of pyelonephritis with progressive anemia (Hb: 6.4). From around March 2014 onwards, when the patient became capable of taking 3-g/day doses consistently, nevertheless, the fever resolved and the abdominal symptoms subsided almost completely, along with improvement of the anemia (Hb: recovered to 11.3). Her general condition had improved significantly as of February 2015.