Mixed responses to targeted therapy driven by chromosomal instability through p53 dysfunction and genome doubling.

The phenomenon of mixed/heterogenous treatment responses to cancer therapies within an individual patient presents a challenging clinical scenario. Furthermore, the molecular basis of mixed intra-patient tumor responses remains unclear. Here, we show that patients with metastatic lung adenocarcinoma harbouring co-mutations of EGFR and TP53, are more likely to have mixed intra-patient tumor responses to EGFR tyrosine kinase inhibition (TKI), compared to those with an EGFR mutation alone. The combined presence of whole genome doubling (WGD) and TP53 co-mutations leads to increased genome instability and genomic copy number aberrations in genes implicated in EGFR TKI resistance. Using mouse models and an in vitro isogenic p53-mutant model system, we provide evidence that WGD provides diverse routes to drug resistance by increasing the probability of acquiring copy-number gains or losses relative to non-WGD cells. These data provide a molecular basis for mixed tumor responses to targeted therapy, within an individual patient, with implications for therapeutic strategies.

Mediation of antitumor activity by AZD4820 oncolytic vaccinia virus encoding IL-12.

Oncolytic viruses are engineered to selectively kill tumor cells and have demonstrated promising results in early-phase clinical trials. To further modulate the innate and adaptive immune system, we generated AZD4820, a vaccinia virus engineered to express interleukin-12 (IL-12), a potent cytokine involved in the activation of natural killer (NK) and T cells and the reprogramming of the tumor immune microenvironment. Testing in cultured human tumor cell lines demonstrated broad in vitro oncolytic activity and IL-12 transgene expression. A surrogate virus expressing murine IL-12 demonstrated antitumor activity in both MC38 and CT26 mouse syngeneic tumor models that responded poorly to immune checkpoint inhibition. In both models, AZD4820 significantly upregulated interferon-gamma (IFN-γ) relative to control mice treated with oncolytic vaccinia virus (VACV)-luciferase. In the CT26 study, 6 of 10 mice had a complete response after treatment with AZD4820 murine surrogate, whereas control VACV-luciferase-treated mice had 0 of 10 complete responders. AZD4820 treatment combined with anti-PD-L1 blocking antibody augmented tumor-specific T cell immunity relative to monotherapies. These findings suggest that vaccinia virus delivery of IL-12, combined with immune checkpoint blockade, elicits antitumor immunity in tumors that respond poorly to immune checkpoint inhibitors.

Tuberculosis and oncogenic HPV: potential co-infections in women at high-risk of cervical cancer in rural China.

The study was embedded in Shanxi Province Cervical Cancer Screening Study II with the aim of examining the association between history of diagnosed tuberculosis or cervical inflammation and oncogenic human papillomavirus (HPV) infection, persistent oncogenic HPV infection, cervical intraepithelial neoplasia grade 3 or cervical cancer (CIN3+) in an isolated rural population of China. A total of 8,798 women were recruited for cervical cancer screening and an interviewer-administered questionnaire. Of the women in the study, 2.7% and 34% reported a diagnosis of tuberculosis and cervical inflammation, respectively. In the model for HPV infection, HPV persistence and CIN3+, we show an increasing magnitude of effect of tuberculosis with increasing severity of disease, as demonstrated by the increasing odds ratios from 1.68 for HPV positivity, to 1.75 for persistent HPV and then 2.08 for CIN3+. Women reporting a diagnosis of tuberculosis, cervical inflammation or both tuberculosis and cervical inflammation were at 75%, 22% and 113% higher odds of persistent HPV infection, respectively. One percent of the study population was diagnosed with tuberculosis and cervical inflammation, placing them at 90% and 113% higher odds of infection with HPV and persistent HPV, respectively. Tuberculosis and oncogenic HPV are identified for the first time as co-infections in rural unscreened women in Shanxi Province, China, highlighting the importance of infection history in assessing an individual' s risk for HPV infection, persistence and CIN3+.

Serum lactate dehydrogenase levels and glycolysis significantly correlate with tumor VEGFA and VEGFR expression in metastatic CRC patients.

OBJECTIVES: In an attempt to elucidate the relationship between biomarkers of tumor hypoxia, glycolysis and angiogenesis, we tested the hypothesis that intratumoral gene expression of the hypoxia response (hypoxia inducible factor [HIF1 alpha and 2 alpha]), glycolysis (lactate dehydrogenase A [LDHA]), glucose metabolism (glucose transporter-1 [Glut-1]) and genes involved in angiogenesis (i.e., VEGFA, VEGFR1-3, and neuropilin [NRP]1) are upregulated in metastatic colorectal cancer (mCRC) patients with high serum lactate dehydrogenase (LDH). PATIENTS AND METHODS: 78 formalin-fixed, paraffin-embedded (FFPE) tumor samples were collected from 36 patients with mCRC. Tumor gene expression was correlated with serum LDH levels from the same group of patients. FFPE tissues were dissected using laser-captured microdissection and analyzed for gene expression using a quantitative real-time RT-PCR method. RESULTS: Intratumoral gene expression of VEGFA and VEGFR1 showed a statistically significant correlation with serum LDH levels (p = 0.006, r = 0.45 and p = 0.004, r = 0.50, respectively). Intratumoral expression of LDHA gene showed a significant correlation with Glut-1, VEGF, HIF1 alpha, HIF2 alpha and VEGFR1 (p = 0.007, r = 0.44; p < 0.001, r = 0.57; p = 0.013, r = 0.41; p = 0.044, r = 0.34; p = 0.026, r = 0.40). Serum LDH levels also correlated with microvessel density analyzed by immunohistochemical analysis. CONCLUSION: The results demonstrated a significant correlation between the intratumoral gene expression of LDHA, HIF1 alpha, HIF2 alpha, Glut-1, NRP1, VEGFA and VEGFR1. Patients with high serum LDH have increased intratumoral gene expression of VEGFA and VEGFR1. The results also support the hypothesis that serum LDH levels may serve as a surrogate marker for activation of the HIF-related genes in the tumor.