Resistance to therapy is the major hurdle in the current cancer management. Cancer cells often rewire their cellular process to alternate mechanisms to resist the deleterious effect mounted by different therapeutic approaches. The major signaling pathways involved in the developmental process, such as Notch, Hedgehog, and Wnt, play a vital role in development, tumorigenesis, and also in the resistance to the various anticancer therapies. Understanding how cancer utilizes these developmental pathways in acquiring the resistance to the multi-therapeutic approach cancer can give rise to a new insight of the anti-therapy resistance mechanisms, which can be explored for the development of a novel therapeutic approach. We present a brief overview of Notch, Hedgehog, and Wnt signaling pathways in cancer and its role in providing resistance to various cancer treatment modalities such as chemotherapy, radiotherapy, molecular targeted therapy, and immunotherapy. Understanding the importance of these molecular networks will provide a rational basis for novel and safer combined anticancer therapeutic approaches for the improvement of cancer treatment by overcoming drug resistance.

The recently described role of RNA methylation in regulating immune cell infiltration into tumors has attracted interest, given its potential impact on immunotherapy response. YTHDF1 is a versatile and powerful m6A reader, but the understanding of its impact on immune evasion is limited. Here, we reveal that tumor-intrinsic YTHDF1 drives immune evasion and immune checkpoint inhibitor (ICI) resistance. Additionally, YTHDF1 deficiency converts cold tumors into responsive hot tumors, which improves ICI efficacy. Mechanistically, YTHDF1 deficiency inhibits the translation of lysosomal genes and limits lysosomal proteolysis of the major histocompatibility complex class I (MHC-I) and antigens, ultimately restoring tumor immune surveillance. In addition, we design a system for exosome-mediated CRISPR/Cas9 delivery to target YTHDF1 in vivo, resulting in YTHDF1 depletion and antitumor activity. Our findings elucidate the role of tumor-intrinsic YTHDF1 in driving immune evasion and its underlying mechanism.

Background: Machine learning (ML) algorithms are increasingly explored in glioma prognostication. Random survival forest (RSF) is a common ML approach in analyzing time-to-event survival data. However, it is controversial which method between RSF and traditional cornerstone method Cox proportional hazards (CPH) is better fitted. The purpose of this study was to compare RSF and CPH in predicting tumor progression of high-grade glioma (HGG) after particle beam radiotherapy (PBRT). Methods: The study enrolled 82 consecutive HGG patients who were treated with PBRT at Shanghai Proton and Heavy Ion Center between 6/2015 and 11/2019. The entire cohort was split into the training and testing set in an 80/20 ratio. Ten variables from patient-related, tumor-related and treatment-related information were utilized for developing CPH and RSF for predicting progression-free survival (PFS). The model performance was compared in concordance index (C-index) for discrimination (accuracy), brier score (BS) for calibration (precision) and variable importance for interpretability. Results: The CPH model demonstrated a better performance in terms of integrated C-index (62.9%) and BS (0.159) compared to RSF model (C-index = 61.1%, BS = 0.174). In the context of variable importance, CPH model indicated that age (P = 0.024), WHO grade (P = 0.020), IDH gene (P = 0.019), and MGMT promoter status (P = 0.040) were significantly correlated with PFS in the univariate analysis; multivariate analysis showed that age (P = 0.041), surgical completeness (P = 0.084), IDH gene (P = 0.057), and MGMT promoter (P = 0.092) had a significant or trend toward the relation with PFS. RSF showed that merely IDH and age were of positive importance for predicting PFS. A final nomogram was developed to predict tumor progression at the individual level based on CPH model. Conclusions: In a relatively small dataset with HGG patients treated with PBRT, CPH outperformed RSF for predicting tumor progression. A comprehensive criterion with accuracy, precision, and interpretability is recommended in evaluating ML prognostication approaches for clinical deployment.

BACKGROUND: Reirradiation for locoregionally recurrent nasopharyngeal carcinoma (NPC) after a definitive dose of radiotherapy (RT) is challenging and usually associated with severe toxicities. Intensity‐modulated carbon ion RT (IMCT) offers physical/biologic advantages over photon‐based intensity‐modulated RT. Herein, the authors report their initial experience of IMCT in previously irradiated patients with locoregionally recurrent NPC.METHODS: Patients with locoregionally recurrent, poorly differentiated or undifferentiated NPC who underwent salvage therapy with IMCT at the Shanghai Proton and Heavy Ion Center between May 2015 and August 2017 were included in the current study. The IMCT doses were 50 to 66 Gray equivalent (GyE) (2.0‐3.0 GyE/daily fraction), delivered via raster scanning technology. The 1‐year overall survival, disease‐specific survival, progression‐free survival (PFS), local recurrence‐free survival, regional recurrence‐free survival, and distant metastasis‐free survival were calculated. Univariate and multivariate analyses of PFS were performed to identify possible predictive factors.RESULTS: Among the 75 patients included, 4 patients, 14 patients, 29 patients, and 28 patients, respectively, had recurrent American Joint Committee on Cancer stage I, stage II, stage III, and stage IVA/B disease. With a median follow‐up of 15.4 months (range, 2.6‐29.7 months), the 1‐year overall survival, disease‐specific survival, PFS, local recurrence‐free survival, regional recurrence‐free survival, and distant metastasis‐free survival rates were 98.1%, 98.1%, 82.2%, 86.6%, 97.9%, and 96.2%, respectively. A higher fraction size of 3 GyE (vs <3 GyE) or a higher biological equivalent dose significantly improved the PFS rate on univariate analysis, but not on multivariate analysis. No patient developed acute toxicity of grade ≥2 during IMCT. Late treatment‐induced severe (grade 3 or 4) toxicities were infrequent, but included mucosal necrosis (9.3%), xerostomia (1.3%), and temporal lobe necrosis (1.3%).CONCLUSIONS: This initial experience in the first 75 patients with locoregionally recurrent NPC was encouraging. Carbon ion RT could provide promising survival rates with infrequent severe toxicities for patients with locoregionally recurrent NPC. Cancer 2018;124:2427‐37. © 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.

Background: Accumulating evidence suggested that radiotherapy can activate anti-tumor immune responses by triggering immunogenic cell death (ICD) of tumor cells. Calreticulin is regarded as one of the most important markers of ICD. The cell surface translocation of calreticulin (ecto-CRT) serves as an “eat me” signal for phagocytosis of dying cells, which plays a pivotal role in activating anti-tumor immunity. However, there is limited knowledge describing the effects of proton and carbon-ion radiation on ecto-CRT exposure. Hence, we investigated ecto-CRT exposure in multiple human carcinoma cell lines irradiated by proton and carbon-ion in comparison to photon. Methods: This study examined four human cancer cell lines including A549 (lung adenocarcinoma), U251MG (glioma), Tca8113 (tongue squamous carcinoma), and CNE-2 (nasopharyngeal carcinoma). Cell lines were irradiated with photon, proton or carbon-ion at 0, 2, 4, 10 Gy (physical dose). The ecto-CRT exposure level was analyzed by flow cytometry at 12, 24, and 48 h post-irradiation. The median fluorescence intensity was calculated by FlowJo. Results: All three types of radial beam increased ecto-CRT exposure of the 4 tumor cell lines in a time-dependent manner. Ecto-CRT exposure significantly elevated 1.5–2.4 times over 48 h post-irradiation compared with controls (P<0.05). Proton and photon increased ecto-CRT exposure with dose escalation. Photon and proton at 10 Gy increased the most ecto-CRT exposure (P<0.05), while carbon-ion increased most ecto-CRT exposure at 4 Gy rather than 10 or 2 Gy. When compared with iso-physical dose at 48 h post-irradiation, proton showed a similar effectiveness with photon. While carbon-ion has significantly stronger effects on increasing ecto-CRT than proton and photon at 2 and 4 Gy, but changed oppositely at 10 Gy (P<0.05). Conclusions: All the three types of radiation can increase the ecto-CRT exposure in a time-dependent manner. Proton and photon radiation were equally effective in inducing ecto-CRT exposure, while carbon-ion revealed a different effectiveness in comparison to photon and proton.

Locally recurrent nasopharyngeal carcinoma (rNPC) after definitive IMRT occurs in 10% of all cases and represents a distinct clinical entity that has been selectively enriched by radio-resistant cancer cells. Therefore, we report of the outcomes of 77 patients who had repeat salvage-IMRT for rNPC after only a definitive course of IMRT. Various clinical outcomes were measured. Log-rank tests were used to detect differences in the survival outcomes between factor-defined subgroups. Multivariable analysis was performed using the Cox proportional hazard model. The median follow-up time was 25.7 months (range 3.0–75.7 months), measured from the time of recurrence. The median OS time and PFS time of the entire cohort was 37.0 and 20.5 months, respectively. Thirty-four patients (44.2%) died. Approximately 35% of these patients died from disease progression, but 53% were from treatment-induced severe adverse effects (SAEs) without evidence of disease progression. Higher T-classification of the recurrent tumor and the development of SAEs were found to be the only independent and significant adverse prognostic factors on multivariable analysis. These outcomes underscore the particularly virulent characteristics of rNPC after definitive IMRT. Concerning is the impact of re-irradiation toxicity on patient mortality.