Use of conditional reprogramming cell, patient derived xenograft and organoid for drug screening for individualized prostate cancer therapy: Current and future perspectives (Review).

Prostate cancer mortality is ranked second among all cancer mortalities in men worldwide. There is a great need for a method of efficient drug screening for precision therapy, especially for patients with existing drug­resistant prostate cancer. Based on the concept of bacterial cell culture and drug sensitivity testing, the traditional approach of cancer drug screening is inadequate. The current and more innovative use of cancer cell culture and in vivo tumor models in drug screening for potential individualization of anti­cancer therapy is reviewed and discussed in the present review. An ideal screening model would have the ability to identify drug activity for the targeted cells resembling what would have occurred in the in vivo environment. Based on this principle, three available cell culture/tumor screening models for prostate cancer are reviewed and considered. The culture conditions, advantages and disadvantages for each model together with ideas to best utilize these models are discussed. The first screening model uses conditional reprogramed cells derived from patient cancer cells. Although these cells are convenient to grow and use, they are likely to have different markers and characteristics from original tumor cells and thus not likely to be informative. The second model employs patient derived xenograft (PDX) which resembles an in vivo approach, but its main disadvantages are that it cannot be easily genetically modified and it is not suitable for high­throughput drug screening. Finally, high­throughput screening is more feasible with tumor organoids grown from patient cancer cells. The last system still needs a large number of tumor cells. It lacks in situ blood vessels, immune cells and the extracellular matrix. Based on these current models, future establishment of an organoid data bank would allow the selection of a specific organoid resembling that of an individual's prostate cancer and used for screening of suitable anticancer drugs. This can be further confirmed using the PDX model. Thus, this combined organoid­PDX approach is expected to be able to provide the drug sensitivity testing approach for individualization of prostate cancer therapy in the near future.

Phase II trial of 131-Iodine tositumomab with high-dose chemotherapy and autologous stem cell transplantation for relapsed diffuse large B cell lymphoma.

The purpose of this study was to evaluate the standard outpatient dose of 131-Iodine tositumomab (75 cGy) combined with high-dose carmustine, etoposide, cytarabine, and melphalan (BEAM) followed by autologous stem cell rescue for the treatment of chemotherapy-sensitive relapsed or refractory, or high-risk first complete remission (CR) patients with diffuse large B cell non-Hodgkin's lymphoma (DLBCL). Forty patients with chemotherapy-sensitive persistent or relapsed or high/intermediate or high international prognostic index DLCBL were treated in a phase II trial combining 75 cGy 131-Iodine tositumomab with high-dose BEAM followed by autologous stem cell transplantation. The CR rate after transplantation was 78%, and the overall response rate was 80%. Short-term and long-term toxicities were similar to historical control patients treated with BEAM alone. With a median follow-up of 6 years (range, 3-10 years), the 5-year overall survival (OS) was 72% (95% confidence interval [CI], 55%-83%), and the 5-year progression-free survival (PFS) rate was 70% (95% CI, 53%-82%). The PFS and OS were encouraging in this group of chemotherapy-sensitive persistent, relapsed, or high-risk patients with DLBCL. A follow-up phase III trial with 131-Iodine tositumomab/BEAM vs rituximab/BEAM was planned based on this information.

Lack of expression of MTAP in uncommon T-cell lymphomas.

UNLABELLED: The majority of peripheral T-cell lymphomas were found to lack methylthioadenosine phosphorylase, an enzyme that is essential for the salvage of adenine from methylthioadenosine, a product of polyamine synthesis. Importantly, tumors that lack this enzyme have been shown to be more sensitive to inhibitors of de novo purine synthesis (6-thioguanine, methotrexate). BACKGROUND: T-cell lymphomas, in particular peripheral T-cell lymphoma (PTCL), angioimmunoblastic T-cell lymphoma (AITL), and anaplastic large cell lymphoma (ALCL), have only limited and noncurative treatment options. PATIENTS AND METHODS: We report here that a high percentage of PTCL, AITL, and ALCL lack the enzyme methylthioadenosine phosphorylase (MTAP), as do T-cell leukemia and T-cell lymphoblastic leukemia. MTAP-deficient cells cannot cleave endogenous methylthioadenosine to adenine and 5-methylthioribose-1-phosphate, a precursor of methionine, and as a result have enhanced sensitivity to inhibitors of de novo purine biosynthesis. A recently introduced antifolate, pralatrexate, which has been shown to inhibit de novo purine biosynthesis, has been approved for treatment of PTCL and may have an increasing role in therapy. An alternative strategy involving coadministration of methylthioadenosine and high-dose 6-thioguanine has been proposed and may prove to be selectively toxic to MTAP-deficient uncommon lymphomas. CONCLUSION: Thus the consequences of MTAP deficiency suggest that new therapeutic interventions for T-cell lymphoma may be feasible.

NCCN task force report: molecular markers in leukemias and lymphomas.

The introduction of targeted therapies has revolutionized treatment and improved outcomes in patients with leukemias and lymphomas. However, many patients experience relapse caused by the persistence of residual malignant cells. Cytogenetic and molecular techniques are increasingly being used to assess and quantify minimal residual disease (MRD). The emergence of advanced technologies has led to the discovery of multiple novel molecular markers that can be used to detect MRD and predict outcome in patients with leukemias and lymphomas. Gene expression signatures that predict clinical outcomes in patients with non-Hodgkin's lymphoma have been identified. In chronic myelogenous leukemia, molecular monitoring has become more important in assessing response and detecting resistance to therapy. In acute leukemias, several new markers have shown potential in prognostication and monitoring treatment. In leukemias and lymphomas, microRNAs have been identified that may be useful in diagnostics and prognostication. To address these issues, the National Comprehensive Cancer Network (NCCN) organized a task force consisting of a panel of experts in leukemia and lymphoma to discuss recent advances in the field of molecular markers and monitoring MRD.