Journal of clinical oncology and research最新文献

Tissue-specific stem cells are the target for selected mutations in oncogenes or tumor suppressor genes that enhance the fitness of these cells, resulting in a self-limited clonal expansion and eventual cancer development. The initial or truncal mutations in the stem cell select for subsequent mutations that enhance their fitness, producing a reproducible order of mutations, selected for in each tissue type, during cancer development. Mutations in stem cells occur randomly, but the selection for increased fitness, occurs non-randomly, conferring a functional order on the selection of mutations. Tissue-specific stem cells are "units of natural selection" for somatic stem cells throughout life. This is why inherited cancer-causing mutations, which, by definition, are initial or truncal mutations, are observed to cause cancers with limited tissue specificities, even though the mutations are present in stem cells for all tissue types. In future studies, we need to understand why the same signal transduction pathways function differently in different tissue-specific stem cells. We also need to understand the truncal mutations for each cancer type, so as to eradicate the stem cell clones for that cancer before they produce a malignant tumor. To accomplish these objectives, we need to carry out new kinds of clinical trials with drugs that target mutations in tissue-specific stem cells.

Radiotherapy (RT) has long been known to be immunogenic. Mounting preclinical data demonstrate a synergistic anti-tumor effect when RT is used in combination with immune check point inhibitors (ICI). However, it is unclear how to best integrate RT with an ICI (i.e. dose fractionation, sequence, etc.). Here we explored the concept that RT delivered as an in situ tumor vaccine sequentially to separate tumors over time might stimulate more potent and rapid antitumor immune response than RT delivered to only one tumor. In essence, radiation to a second tumor could be likened to giving a vaccine "booster shot". Mice bearing pancreatic tumors in three different sites were injected with anti-PD-L1 antibody and exposed to three daily consecutive fractions of 4 Gy each at one or two sites with a one week interval. Our data indicate that delivering an RT to one tumor followed by an RT "booster shot" to a second tumor, compared to treating only one tumor with RT, significantly reduced tumor growth at a third non-irradiated site. This abscopal effect to the non-irradiated site was observed earlier (day 9) in mice that received RT to two tumors versusa single tumor (day 17). Decreased growth of the non-irradiated tumor correlated with a transient increase of the CD4/CD8 ratio in the tumor, increase myeloid-derived suppressor cells and tumor associated macrophages in the draining lymph nodes. These data warrant further exploration of sequentially treating multiple lesions with RT and ICI with the intent of generating a robust anti-tumor immune response.

Purpose: Weight gain after a breast cancer diagnosis is associated with poor cancer outcomes. Limited research describes patterns of weight change by race. The goal of this study was to assess and compare the percent of weight change and change in body mass index (BMI) after chemotherapy in Black and White breast cancer patients.

Methods: Black and White women diagnosed with invasive non-metastatic breast cancer were recruited from two metropolitan areas. Medical records were abstracted to obtain clinical (e.g. cancer stage) and treatment variables (e.g. chemotherapy regimen). Weight change was examined in 98 women who underwent chemotherapy. Differences in baseline characteristics by race were evaluated using the chi-square or Fisher's exact test for categorical variables and t-test for continuous variables. We performed bivariate associations between study variables and relative weight change.

Results: Most (62%) participants maintained their pre-treatment weight; 38% gained more than 5% of their baseline weight by the end chemotherapy. Normal weight women had the highest mean increase (3.57; 1.05, 6.10) compared to those that were overweight/obese. Fifteen percent of women shifted to a higher BMI category; 26% of those that were normal became overweight; 17% of overweight patients became obese. Blacks were more likely than whites to shift to a higher BMI (P=0.06).

Conclusions: Results underscore the need for integrating weight control within cancer treatment plans to prevent weight gain in patients undergoing chemotherapy. Future studies that help to elucidate behaviors and/or biological factors that contribute to weight gain overall and in blacks will be important.

Chemotherapy remains of limited use for the treatment of prostate cancer with only one drug, docetaxel, demonstrating a modest survival advantage for treatment of late-stage disease. Data from the NCI 60 cell line screen indicated that the castration-resistant prostate cancer cell lines PC3 and DU145 were more sensitive than average to the novel polymeric fluoropyrimidine (FP), F10, despite displaying less than average sensitivity to the widely-used FP, 5FU. Here, we show that F10 treatment of PC3 xenografts results in a significant survival advantage (treatment to control ratio (T/C) days = 18; p < 0.001; n = 16) relative to control mice treated with saline. F10 (40 mg/kg/dose) was administered via jugular vein catheterization 3-times per week for five weeks. This aggressive dosing regimen was completed with no drug-induced weight loss and with no evidence of toxicity. F10 was also shown to sensitize PC3 cells to radiation and F10 was also shown to be a potent radiosensitizer of PC3 xenografts in vivo with F10 in combination with radiation resulting in significantly greater regression of PC3 xenografts than radiation alone. The results indicate that F10 in this pre-clinical setting is an effective chemotherapeutic agent and possesses significant radiosensitizing properties.

Glioblastoma multiforme (GBM) is a very aggressive and locally invasive tumor. The current standard of care is partial brain radiation therapy (60 Gy) concurrently with the alkylating agent temozolomide (TMZ). However, patients' survival remains poor (6-12 months) mainly due to local and diffuse (distant) recurrence. The possibility to promote hyper radiosensitivity (HRS) with low dose radiation may contribute to improve outcome. Here, we evaluated the effect of Vorinostat^SAHA and TMZ on glioblastoma cells' sensitivity to low dose radiation. Clonogenic survivals were performed on D54 (p53 and PTEN wild type) and U118 (p53 and PTEN mutants) cells exposed to clinically relevant doses of Vorinostat^SAHA and TMZ and increasing radiation doses. Apoptosis was measured by the activation of caspase-3 and the role of p53 and PTEN were evaluated with the p53 inhibitor pifithrin α and the PI3K/AKT pathway inhibitor LY29002. Vorinostat^SAHA promoted HRS at doses as low as 0.25 Gy in the D54 but not the U118 cells. Killing efficiency was associated with caspase-3 activation, delayed H2AX phosphorylation and abrogation of a radiation -induced G2 arrest. Inhibiting p53 function with pifithrin α prevented the promotion of HRS by Vorinostat^SAHA. Moreover, LY29002, a PI-3K inhibitor, restored promotion of HRS by Vorinostat^SAHA in the p53 mutant U118 cells to levels similar to the p53 wild type cells. TMZ also promoted HRS at doses as low as 0.15 Gy. These finding indicate that HRS can be promoted in p53 wild type glioblastoma cells through a functional PTEN to delay DNA repair and sensitize cells to low dose radiation. Promotion of HRS thus appears to be a viable approach for GBM that could be used as a basis to develop new Phase I/II studies.