The cost-effectiveness of iruplinalkib versus alectinib in anaplastic lymphoma kinase-positive crizotinib-resistant advanced non-small-cell lung cancer patients in China.

Background: Iruplinalkib is a second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) with efficacy in patients with ALK-positive crizotinib-resistant advanced non-small cell lung cancer (NSCLC), which is independently developed by a Chinese pharmaceutical company. This study examined the cost-effectiveness of iruplinalkib versus alectinib in the Chinese healthcare setting. Methods: A partitioned survival model was developed to project the economic and health outcomes. Efficacy was derived using unanchored matching-adjusted indirect comparison (MAIC). Cost and utility values were obtained from the literature and experts' opinions. Deterministic and probabilistic sensitivity analyses (PSA) were carried out to evaluate the model's robustness. Results: Treatment with iruplinalkib versus alectinib resulted in a gain of 0.843 quality-adjusted life years (QALYs) with incremental costs of $20,493.27, resulting in an incremental cost-effectiveness ratio (ICER) of $24,313.95/QALY. Parameters related to relative efficacy and drug costs were the main drivers of the model outcomes. From the PSA, iruplinalkib had a 90% probability of being cost-effective at a willingness-to-pay threshold of $37,863.56/QALY. Conclusion: Compared to alectinib, iruplinalkib is a cost-effective therapy for patients with ALK-positive crizotinib-resistant advanced NSCLC.

Potential tools for predicting response to chemotherapy in OC: Assessment of immune dysbiosis, participant's self-rated health and microbial dynamics.

Epithelial ovarian cancer (OC) is the deadliest female reproductive cancer; an estimated 13,270 women will die from OC in 2023. Platinum-based chemotherapy resistance mechanisms contribute to poor OC 5-year survival rates. Peripheral inflammation is linked to various disease states and we previously identified unique peritoneal microbial features predictive of OC. We hypothesized that unique peripheral immune profiles and peritoneal microbial features may be predictive of disease-free interval (time to recurrence) and response to chemotherapy in participants with OC. We also investigated self-rated health (SRH) scores in the context of peripheral inflammation as a potential screening tool for OC. Blood and peritoneal fluid were collected from participants with OC or a benign adnexal mass (BPM). Lymphocyte populations were analyzed using Fluorescence Activated Cell Sorting, serum cytokine levels were analyzed using the Human Th17 Magnetic Bead Panel assay and peritoneal fluid microbial features were analyzed using Next Generation Sequencing (NGS). Participants completed a standardized questionnaire on self-rated physical and emotional health. Participants were classified into three chemotherapy response categories: platinum-refractory, platinum-resistant or platinum-sensitive. A significant positive correlation was found between elevated inflammatory status on the day of surgery and longer disease-free interval. SRH measures did not correlate with immune status in participants with OC or a BPM. We identified a correlation between peritoneal microbial features and chemotherapy response. We conclude that immune dysbiosis may be useful in predicting OC recurrence. The immune findings reported here set the framework for additional studies utilizing immune profiles to predict platinum-based chemotherapy responsiveness in OC.

Assessment of algorithms for identifying patients with triple-class refractory multiple myeloma using real-world data.

Objective: Patients with triple-class refractory (TCR) multiple myeloma (MM) have limited treatment options and poor prognoses. This high unmet need has prompted the development of new therapies allowing for improved outcomes for these patients. Recently, new targeted therapies for the treatment of patients with relapsed or refractory MM have been approved based on single-arm clinical trial results. Real-world (RW) data enable a better understanding of the effectiveness of new therapies in clinical practice and provide external controls for single-arm studies. However, using RW data to identify patients with TCR MM is challenging and subject to limitations. Methods: In this retrospective cohort study of an analysis of the COTA electronic health record (EHR) database, we used four algorithms to define refractory status and created four groups of patients with TCR MM initiating post-TCR therapy. Each algorithm relied on slightly different criteria to identify TCR patients, but all were based on the International Myeloma Working Group (IMWG)-derived and/or healthcare provider (HCP)-reported progressions within the database. Results: A total of 3815 patients with newly diagnosed MM met the eligibility criteria for this study. The choice of the algorithm did not impact the characteristics of identified patients with TCR MM (Algorithm 1 [n = 404], Algorithm 2 [n = 123], Algorithm 3 [n = 404], and Algorithm 4 [n = 375]), including their demographic and disease characteristics, MM treatment history, or treatment patterns received after becoming TCR. However, identifying TCR MM using a combination of IMWG-derived and HCP-reported progressions allowed up to a 70% increase in the size of the identified group of patients compared with using only IMWG-derived progressions. Conclusion: In RW settings, progressions from both IMWG-derived data and physician reports may be used to identify patients with TCR MM.

Noninvasive minimal residual disease assessment in relapsed/refractory large B-cell lymphoma using digital droplet PCR.

Although several promising approaches for the treatment of relapsed/refractory diffuse large B-cell lymphoma (rrDLBCL) have been approved recently, it remains unclear which patients will ultimately achieve long-term responses. Circulating tumor (ct)DNA sequencing has emerged as a valuable tool to assess minimal residual disease (MRD). Correlations between MRD and outcomes have been shown in previously untreated DLBCL, but data on the repeated assessment of MRD in the dynamic course of rrDLBCL is limited. Here, we present an approach leveraging cost- and time-sensitivity of digital droplet (dd)PCR to repeatedly assess MRD in rrDLBCL and present proof-of-principle for its ability to predict outcomes.

The EMA Assessment of Asciminib for the Treatment of Adult Patients With Philadelphia Chromosome-Positive Chronic Myeloid Leukemia in Chronic Phase Who Were Previously Treated With at Least Two Tyrosine Kinase Inhibitors.

Asciminib is an allosteric high-affinity tyrosine kinase inhibitor (TKI) of the BCR-ABL1 protein kinase. This kinase is translated from the Philadelphia chromosome in chronic myeloid leukemia (CML). Marketing authorization for asciminib was granted on August 25, 2022 by the European Commission. The approved indication was for patients with Philadelphia chromosome-positive CML in the chronic phase which have previously been treated with at least 2 TKIs. Clinical efficacy and safety of asciminib were evaluated in the open-label, randomized, phase III ASCEMBL study. The primary endpoint of this trial was major molecular response (MMR) rate at 24 weeks. A significant difference in MRR rate was shown between the asciminib treated population and the bosutinib control group (25.5% vs. 13.2%, respectively, P = .029). In the asciminib cohort, adverse reactions of at least grade 3 with an incidence ≥ 5% were thrombocytopenia, neutropenia, increased pancreatic enzymes, hypertension, and anemia. The aim of this article is to summarize the scientific review of the application which led to the positive opinion by the European Medicines Agency's Committee for Medicinal Products for Human Use.

Patient-derived cell-based pharmacogenomic assessment to unveil underlying resistance mechanisms and novel therapeutics for advanced lung cancer.

BACKGROUND: A pharmacogenomic platform using patient-derived cells (PDCs) was established to identify the underlying resistance mechanisms and tailored treatment for patients with advanced or refractory lung cancer. METHODS: Drug sensitivity screening and multi-omics datasets were acquired from lung cancer PDCs (n = 102). Integrative analysis was performed to explore drug candidates according to genetic variants, gene expression, and clinical profiles. RESULTS: PDCs had genomic characteristics resembled with those of solid lung cancer tissues. PDC molecular subtyping classified patients into four groups: (1) inflammatory, (2) epithelial-to-mesenchymal transition (EMT)-like, (3) stemness, and (4) epithelial growth factor receptor (EGFR)-dominant. EGFR mutations of the EMT-like subtype were associated with a reduced response to EGFR-tyrosine kinase inhibitor therapy. Moreover, although RB1/TP53 mutations were significantly enriched in small-cell lung cancer (SCLC) PDCs, they were also present in non-SCLC PDCs. In contrast to its effect in the cell lines, alpelisib (a PI3K-AKT inhibitor) significantly inhibited both RB1/TP53 expression and SCLC cell growth in our PDC model. Furthermore, cell cycle inhibitors could effectively target SCLC cells. Finally, the upregulation of transforming growth factor-ß expression and the YAP/TAZ pathway was observed in osimertinib-resistant PDCs, predisposing them to the EMT-like subtype. Our platform selected XAV939 (a WNT-TNKS-ß-catenin inhibitor) for the treatment of osimertinib-resistant PDCs. Using an in vitro model, we further demonstrated that acquisition of osimertinib resistance enhances invasive characteristics and EMT, upregulates the YAP/TAZ-AXL axis, and increases the sensitivity of cancer cells to XAV939. CONCLUSIONS: Our PDC models recapitulated the molecular characteristics of lung cancer, and pharmacogenomics analysis provided plausible therapeutic candidates.

Dynamic Assessment of Tissue and Plasma EGFR-Activating and T790M Mutations with Droplet Digital PCR Assays for Monitoring Response and Resistance in Non-Small Cell Lung Cancers Treated with EGFR-TKIs.

Assessing tumor EGFR mutation status is necessary for the proper management of patients with advanced non-small cell lung cancer (NSCLC). We evaluated the impact of dynamic analyses of the plasma and tissue EGFR mutation using ultra-sensitive droplet digital PCR (ddPCR) assays to manage NSCLC patients treated with EGFR tyrosine kinase inhibitors (EGFR-TKIs). Paired tumor tissues and plasma samples from 137 EGFR-mutated lung adenocarcinoma patients prior to the first-line EGFR-TKIs treatment (at baseline) and at disease progression were subjected to EGFR mutation analysis using ddPCR, together with the analyses of the clinicopathological characteristics and treatment outcomes. Patients with EGFR-activating mutations detected in baseline plasma were associated with bone metastasis (p = 0.002) and had shorter progression-free survival (12.9 vs. 17.7 months, p = 0.02) and overall survival (24.0 vs. 39.4 months, p = 0.02) compared to those without. Pre-treatment EGFR T790M mutation found in baseline tumor tissues of 28 patients (20.4%; 28/137) was significantly associated with brain metastasis (p = 0.005) and a shorter brain metastasis-free survival (p = 0.001). The presence of EGFR T790M mutations in baseline tumor tissues did not correlate with the emergence of acquired EGFR T790M mutations detected at progression. At disease progression, acquired EGFR T790M mutations were detected in 26.6% (21/79) of the plasma samples and 42.9% (15/35) of the rebiopsy tissues, with a concordance rate of 71.4% (25/35). The dynamic monitoring of tissue and plasma EGFR mutation status at baseline and progression using ddPCR has a clinical impact on the evaluation of EGFR-TKIs treatment efficacy and patient outcomes, as well as the emergence of resistance in NSCLC.

Ex vivo assessment of cancer drug sensitivity in epithelial ovarian cancer and its association with histopathological type, treatment history and clinical outcome.

Epithelial ovarian cancer (EOC) is divided into type I and type II based on histopathological features. Type I is clinically more indolent, but also less sensitive to chemotherapy, compared with type II. The basis for this difference is not fully clarified. The present study investigated the pattern of drug activity in type I and type II EOC for standard cytotoxic drugs and recently introduced tyrosine kinase inhibitors (TKIs), and assessed the association with treatment history and clinical outcome. Isolated EOC tumor cells obtained at surgery were investigated for their sensitivity to seven standard cytotoxic drugs and nine TKIs using a short­term fluorescent microculture cytotoxicity assay (FMCA). Drug activity was compared with respect to EOC subtype, preoperative chemotherapy, cross­resistance and association with progression­free survival (PFS). Out of 128 EOC samples, 120 samples, including 21 type I and 99 type II, were successfully analyzed using FMCA. Patients with EOC type I had a significantly longer PFS time than patients with EOC type II (P=0.01). In line with clinical experience, EOC type I samples were generally more resistant than type II samples to both standard cytotoxic drugs and the TKIs, reaching statistical significance for cisplatin (P=0.03) and dasatinib (P=0.002). A similar pattern was noted in samples from patients treated with chemotherapy prior to surgery compared with treatment­naive samples, reaching statistical significance for fluorouracil, irinotecan, dasatinib and nintedanib (all P<0.05). PFS time gradually shortened with increasing degree of drug resistance. Cross­resistance between drugs was in most cases statistically significant yet moderate in degree (r<0.5). The clinically observed relative drug resistance of EOC type I, as well as in patients previously treated, is at least partly due to mechanisms in the tumor cells. These mechanisms seemingly also encompass kinase inhibitors. Ex vivo assessment of drug activity is suggested to have a role in the optimization of drug therapy in EOC.

Different costs of therapeutic resistance in cancer: Short- and long-term impact of population heterogeneity.

Therapeutic resistance continues to undercut long-term success of many promising cancer treatments. At times, development of therapeutic resistance can come at a fitness cost for the cancer cell population, which could potentially be leveraged to the patient's advantage. A mathematical formulation of such a situation was proposed by Pressley et al. (2020), who discussed two scenarios, namely, when developing therapeutic resistance can come at a cost to proliferative capacity (such as when a drug targets a growth receptor), or to the total tumor carrying capacity (such as when a drug targets neovascularization). Here we expand the analysis of the two models and evaluate both short- and long-term dynamics of a population heterogeneous with respect to resistance. We analyze four initial distributions with respect to resistance at the time of treatment initiation: uniform, bell-shaped, exponential, and U-shaped. We show that final population composition is invariant to the initial distribution, with a single clone eventually dominating within the population; the value of the resistance parameter of the final clone depends on other system parameters but not on the initial distribution. Transitional behaviors, however, which may have more significant implications for immediate treatment decisions, depend critically on the initial distribution. Furthermore, we show that depending on the mechanism for the cost of resistance (i.e., proliferation vs carrying capacity), increase in natural cell death rate has opposite effects, with higher natural death rate selecting for less resistant cell clones in the long term for proliferation-dependent model, and selecting for more resistant cell clones for carrying capacity-dependent model, a prediction that may have implications for combination therapy with cytotoxic agents. We conclude with a discussion of strengths and limitations of using modeling for understanding treatment trajectory, as well as the promise of model-informed evolutionary steering for improved long-term therapeutic outcomes.

Mitochondrial adaptation in cancer drug resistance: prevalence, mechanisms, and management.

Drug resistance represents a major obstacle in cancer management, and the mechanisms underlying stress adaptation of cancer cells in response to therapy-induced hostile environment are largely unknown. As the central organelle for cellular energy supply, mitochondria can rapidly undergo dynamic changes and integrate cellular signaling pathways to provide bioenergetic and biosynthetic flexibility for cancer cells, which contributes to multiple aspects of tumor characteristics, including drug resistance. Therefore, targeting mitochondria for cancer therapy and overcoming drug resistance has attracted increasing attention for various types of cancer. Multiple mitochondrial adaptation processes, including mitochondrial dynamics, mitochondrial metabolism, and mitochondrial apoptotic regulatory machinery, have been demonstrated to be potential targets. However, recent increasing insights into mitochondria have revealed the complexity of mitochondrial structure and functions, the elusive functions of mitochondria in tumor biology, and the targeting inaccessibility of mitochondria, which have posed challenges for the clinical application of mitochondrial-based cancer therapeutic strategies. Therefore, discovery of both novel mitochondria-targeting agents and innovative mitochondria-targeting approaches is urgently required. Here, we review the most recent literature to summarize the molecular mechanisms underlying mitochondrial stress adaptation and their intricate connection with cancer drug resistance. In addition, an overview of the emerging strategies to target mitochondria for effectively overcoming chemoresistance is highlighted, with an emphasis on drug repositioning and mitochondrial drug delivery approaches, which may accelerate the application of mitochondria-targeting compounds for cancer therapy.

Assessment of Tumor Heterogeneity in High-Grade Serous Ovarian Cancer: Mass Cytometry to Understand the Complex Tumor Biology.

Ovarian cancer (OC) is the most deadly gynecological malignancy worldwide. OC patients undergo debulking surgery followed by platinum/taxane-based chemotherapy; however, despite recent development of new therapeutic approaches based on combination of chemotherapy and innovative targeted-therapies, most of them relapse due to chemoresistance. Many studies have been carried out to decipher the high heterogeneity of ovarian cancer cells that drives tumor treatment failure. Here, we describe our experience in the characterization of ovarian cancer cell subsets through a high-resolution technology in multiparametric analysis, such as mass cytometry (MC).

Analysis of Multiple Drug Resistance Mechanism in Different Types of Soft Tissue Sarcomas: Assessment of the Expression of ABC-Transporters, MVP, YB-1, and Analysis of Their Correlation with Chemosensitivity of Cancer Cells.

Chemotherapy of soft tissue sarcomas (STS) is restricted by low chemosensitivity and multiple drug resistance (MDR). The purpose of our study was the analysis of MDR mechanism in different types of STS. We assessed the expression of ABC-transporters, MVP, YB-1, and analyzed their correlation with chemosensitivity of cancer cells. STS specimens were obtained from 70 patients without metastatic disease (2018-2020). Expression level of MDR-associated genes was estimated by qRT-PCR and cytofluorimetry. Mutations in ABC-transporter genes were captured by exome sequencing. Chemosensitivity (SI) of STS to doxorubicin (Dox), ifosfamide (Ifo), gemcitabine (Gem), and docetaxel (Doc) was analyzed in vitro. We found strong correlation in ABCB1, ABCC1, and ABCG2 expression. We demonstrated strong negative correlations in ABCB1 and ABCG2 expression with SI (Doc) and SI (Doc + Gem), and positive correlation of MVP expression with SI (Doc) and SI (Doc + Gem) in undifferentiated pleomorphic sarcoma. Pgp expression was shown in 5 out of 44 STS samples with prevalence of synovial sarcoma relapses and it is strongly correlated with SI (Gem). Mutations in MDR-associated genes were rarely found. Overall, STS demonstrated high heterogeneity in chemosensitivity that makes reasonable in vitro chemosensitivity testing to improve personalized STS therapy, and classic ABC-transporters are not obviously involved in MDR appearance.

Functional In Vitro Assessment of VEGFA/NOTCH2 Signaling Pathway and pRB Proteasomal Degradation and the Clinical Relevance of Mucolipin TRPML2 Overexpression in Glioblastoma Patients.

Glioblastoma (GBM) is the most malignant glioma with an extremely poor prognosis. It is characterized by high vascularization and its growth depends on the formation of new blood vessels. We have previously demonstrated that TRPML2 mucolipin channel expression increases with the glioma pathological grade. Herein by ddPCR and Western blot we found that the silencing of TRPML2 inhibits expression of the VEGFA/Notch2 angiogenic pathway. Moreover, the VEGFA/Notch2 expression increased in T98 and U251 cells stimulated with the TRPML2 agonist, ML2-SA1, or by enforced-TRPML2 levels. In addition, changes in TRPML2 expression or ML2-SA1-induced stimulation, affected Notch2 activation and VEGFA release. An increased invasion capability, associated with a reduced VEGF/VEGFR2 expression and increased vimentin and CD44 epithelial-mesenchymal transition markers in siTRPML2, but not in enforced-TRPML2 or ML2-SA1-stimulated glioma cells, was demonstrated. Furthermore, an increased sensitivity to Doxorubicin cytotoxicity was demonstrated in siTRPML2, whereas ML2-SA1-treated GBM cells were more resistant. The role of proteasome in Cathepsin B-dependent and -independent pRB degradation in siTRPML2 compared with siGLO cells was studied. Finally, through Kaplan-Meier analysis, we found that high TRPML2 mRNA expression strongly correlates with short survival in GBM patients, supporting TRPML2 as a negative prognostic factor in GBM patients.

Experimental and computational assessment of the synergistic pharmacodynamic drug-drug interactions of a triple combination therapy in refractory HER2-positive breast cancer cells.

The development of innate and/or acquired resistance to human epidermal growth factor receptor type-2 (HER2)-targeted therapy in HER2-positive breast cancer (HER2 + BC) is a major clinical challenge that needs to be addressed. One of the main mechanisms of resistance includes aberrant activation of the HER2 and phosphatidylinositol 3-kinase/AKT8 virus oncogene cellular homolog/mammalian target of rapamycin (PI3K/Akt/mTOR) pathways. In the present work, we propose to use a triple combination therapy to combat this resistance phenomenon. Our strategy involves evaluation of two targeted small molecule agents, everolimus and dasatinib, with complementary inhibitory circuitries in the PI3K/Akt/mTOR pathway, along with a standard cytotoxic agent, paclitaxel. Everolimus inhibits mTOR, while dasatinib inhibits Src, which is a protein upstream of Akt. An over-activation of these two proteins has been implicated in approximately 50% of HER2 + BC cases. Hence, we hypothesize that their simultaneous inhibition may lead to enhanced cell-growth inhibition. Moreover, the potent apoptotic effects of paclitaxel may help augment the overall cytotoxicity of the proposed triple combination in HER2 + BC cells. To this end, we investigated experimentally and assessed computationally the in vitro pharmacodynamic drug-drug interactions of the various dual and triple combinations to assess their subsequent combinatorial effects (synergistic/additive/antagonistic) in a HER2-therapy resistant BC cell line, JIMT-1. Our proposed triple combination therapy demonstrated synergism in JIMT-1 cells, thus corroborating our hypothesis. This effort may form the basis for further investigation of the triple combination therapy in vivo at a mechanistic level in HER2-therapy resistant BC cells.

Assessment of immune biomarkers and establishing a triple negative phenotype in gynecologic cancers.

OBJECTIVE: Immuno-oncology (IO) has rapidly evolved, with many IO therapies either approved or under investigation for multiple malignancies. Biomarkers exist that can predict response to IO therapies including PD-L1 expression, microsatellite instability (MSI), and total mutation burden (TMB). This paper serves to analyze the presence of these biomarkers across gynecologic cancers. METHODS: A total of 16,300 gynecologic cancer specimens submitted for molecular profiling to Caris Life Sciences were reviewed. Immunohistochemistry was performed using the SP142 anti-PD-L1 clone and assessed for intensity. Next-generation sequencing, immunohistochemistry, and fragment analysis were used to determine MSI status. TMB was measured by counting all non-synonymous missense mutations found per tumor not previously described as germline alterations. Chi-Square, Fisher Exact, and the Kruskal-Wallis test were used to compare cohorts. RESULTS: Of 16,300 specimens, 54.1% were ovarian, 37.2% uterine, 7.2% cervical, 0.3% vulvar, 1.2% vaginal, with 0.1% unspecified. MSI-H was most frequent in uterine cancer (17.7%) and only 1% of ovarian cancers. PD-L1 expression was present in 38.3% of cervical and 62.5% of vulvar cancers, but less than 8% of ovarian and uterine cancers. TMB-H was present in 21.1% cervical, 19.7% uterine, and 5% ovarian cancers. Few specimens exhibited a "triple positive" phenotype - 0.3% ovarian, 1.5% uterine, and 1.5% cervical. Associations were seen between MSI, TMB, and PD-L1 across all cancer types. CONCLUSIONS: The frequency of individual biomarkers pertinent to IO therapy varies by cancer type. HPV-driven genital tract cancers have higher frequencies of PD-L1 expression, MSI-H, and TMBH. Endometrial cancers are characterized by MSI-H and TMB, whereas ovarian cancers have a low frequency of MSI-H and modest PD-L1 or TMBH. The incidence of 'triple positive" cases was less than 2%.

A descriptive cost-analysis of MYX.1/MCRN003, a phase 2 clinical trial evaluating high-dose weekly carfilzomib, cyclophosphamide, and dexamethasone in relapsed and refractory multiple myeloma.

BACKGROUND: The prevalence of multiple myeloma is increasing and there is a need to evaluate escalating therapy costs (Canadian Cancer Statistics A, 2020). The MYX.1 phase II trial showed that high-dose weekly carfilzomib, cyclophosphamide, and dexamethasone (wKCD) is efficacious in relapsed and refractory disease. We conducted a descriptive cost analysis, from the perspective of the Canadian public healthcare system, using trial data. METHODS: The primary outcome was the mean total cost per patient. Resource utilization data were collected from all 75 trial patients over a trial time horizon. Costs are presented in Canadian dollars (2020). RESULTS: The cost of treatment was calculated from the time of patient (pt) enrollment until the second data lock. The mean total cost was $203 336.08/pt (range $17 891.27-$505 583.55) Canadian dollars (CAD, where 1 CAD = 0.67 Euro (EUR)) and $14 081.45/pt per cycle. The median number of cycles was 15. The predominant cost driver was the cost of chemotherapy accounting for an average of $179 332.78/pt or $12 419.17/pt per cycle. Carfilzomib acquisition accounted for the majority of chemotherapy costs - $162 471.65/pt or $11 251.50/pt per cycle. Fifty-six percent (56%) of patients had at least one hospitalization during the trial period with an average cost of $12 657.86 per hospitalization. Three patients developed thrombotic microangiopathy (TMA) with an average cost of $18 863.32/pt including the cost of hospitalizations and therapeutic plasma exchange. CONCLUSIONS: High-dose wKCD is an active triplet regimen for relapsed and refractory multiple myeloma (RRMM) associated with reduced total cost compared with twice-weekly carfilzomib-based regimens.

Discovering novel cancer bio-markers in acquired lapatinib resistance using Bayesian methods.

Signalling transduction pathways (STPs) are commonly hijacked by many cancers for their growth and malignancy, but demystifying their underlying mechanisms is difficult. Here, we developed methodologies with a fully Bayesian approach in discovering novel driver bio-markers in aberrant STPs given high-throughput gene expression (GE) data. This project, namely 'PathTurbEr' (Pathway Perturbation Driver) uses the GE dataset derived from the lapatinib (an EGFR/HER dual inhibitor) sensitive and resistant samples from breast cancer cell lines (SKBR3). Differential expression analysis revealed 512 differentially expressed genes (DEGs) and their pathway enrichment revealed 13 highly perturbed singalling pathways in lapatinib resistance, including PI3K-AKT, Chemokine, Hippo and TGF-$\beta $ singalling pathways. Next, the aberration in TGF-$\beta $ STP was modelled as a causal Bayesian network (BN) using three MCMC sampling methods, i.e. Neighbourhood sampler (NS) and Hit-and-Run (HAR) sampler that potentially yield robust inference with lower chances of getting stuck at local optima and faster convergence compared to other state-of-art methods. Next, we examined the structural features of the optimal BN as a statistical process that generates the global structure using $p_1$-model, a special class of Exponential Random Graph Models (ERGMs), and MCMC methods for their hyper-parameter sampling. This step enabled key drivers identification that drive the aberration within the perturbed BN structure of STP, and yielded 34, 34 and 23 perturbation driver genes out of 80 constituent genes of three perturbed STP models of TGF-$\beta $ signalling inferred by NS, HAR and MH sampling methods, respectively. Functional-relevance and disease-relevance analyses suggested their significant associations with breast cancer progression/resistance.

Design and Synthesis of Non-Covalent Imidazo[1,2-a]quinoxaline-Based Inhibitors of EGFR and Their Anti-Cancer Assessment.

A series of 30 non-covalent imidazo[1,2-a]quinoxaline-based inhibitors of epidermal growth factor receptor (EGFR) were designed and synthesized. EGFR inhibitory assessment (against wild type) data of compounds revealed 6b, 7h, 7j, 9a and 9c as potent EGFRWT inhibitors with IC50 values of 211.22, 222.21, 193.18, 223.32 and 221.53 nM, respectively, which were comparable to erlotinib (221.03 nM), a positive control. Furthermore, compounds exhibited excellent antiproliferative activity when tested against cancer cell lines harboring EGFRWT; A549, a non-small cell lung cancer (NSCLC), HCT-116 (colon), MDA-MB-231 (breast) and gefitinib-resistant NSCLC cell line H1975 harboring EGFRL858R/T790M. In particular, compound 6b demonstrated significant inhibitory potential against gefitinib-resistant H1975 cells (IC50 = 3.65 µM) as compared to gefitinib (IC50 > 20 µM). Moreover, molecular docking disclosed the binding mode of the 6b to the domain of EGFR (wild type and mutant type), indicating the basis of inhibition. Furthermore, its effects on redox modulation, mitochondrial membrane potential, cell cycle analysis and cell death mode in A549 lung cancer cells were also reported.

Assessment of tumor hypoxia and perfusion in recurrent glioblastoma following bevacizumab failure using MRI and 18F-FMISO PET.

Tumoral hypoxia correlates with worse outcomes in glioblastoma (GBM). While bevacizumab is routinely used to treat recurrent GBM, it may exacerbate hypoxia. Evofosfamide is a hypoxia-targeting prodrug being tested for recurrent GBM. To characterize resistance to bevacizumab and identify those with recurrent GBM who may benefit from evofosfamide, we ascertained MRI features and hypoxia in patients with GBM progression receiving both agents. Thirty-three patients with recurrent GBM refractory to bevacizumab were enrolled. Patients underwent MR and 18F-FMISO PET imaging at baseline and 28 days. Tumor volumes were determined, MRI and 18F-FMISO PET-derived parameters calculated, and Spearman correlations between parameters assessed. Progression-free survival decreased significantly with hypoxic volume [hazard ratio (HR) = 1.67, 95% confidence interval (CI) 1.14 to 2.46, P = 0.009] and increased significantly with time to the maximum value of the residue (Tmax) (HR = 0.54, 95% CI 0.34 to 0.88, P = 0.01). Overall survival decreased significantly with hypoxic volume (HR = 1.71, 95% CI 1.12 to 12.61, p = 0.01), standardized relative cerebral blood volume (srCBV) (HR = 1.61, 95% CI 1.09 to 2.38, p = 0.02), and increased significantly with Tmax (HR = 0.31, 95% CI 0.15 to 0.62, p < 0.001). Decreases in hypoxic volume correlated with longer overall and progression-free survival, and increases correlated with shorter overall and progression-free survival. Hypoxic volume and volume ratio were positively correlated (rs = 0.77, P < 0.0001), as were hypoxia volume and T1 enhancing tumor volume (rs = 0.75, P < 0.0001). Hypoxia is a key biomarker in patients with bevacizumab-refractory GBM. Hypoxia and srCBV were inversely correlated with patient outcomes. These radiographic features may be useful in evaluating treatment and guiding treatment considerations.

Comparative assessment of three different second-line regimens in chemotherapy resistant / refractory small-cell lung cancer.

PURPOSE: Small cell lung cancer (SCLC) patients unresponsive or relapsing within 90 days following frontline chemotherapy have poor prognosis and they should be treated with different chemotherapy regimens other than those used in the first-line regimen. Currently there is no globally accepted standard chemotherapeutic regimen for the treatment of these patients. This retrospective study was designed to compare CAV (Cyclophosphamide, Doxorubicin, Vincristine), weekly topotecan and weekly irinotecan regimens and to evaluate the efficacy of the three regimens in patients with chemotherapy resistant/refractory (CRR) SCLC. METHODS: A total of 67 CRR-SCLC patients, who were treated with CAV, weekly topotecan and weekly irinotecan were reviewed for weekly irinotecan (27 for 60 mg/m2 intravenously on days 1, 8 and 15 of a 28-day cycle,24 for CAV (Cyclophosphamide 750 mg/m² on day 1, Doxorubicin 50 mg/m² on day 1 and Vincristine 1.4mg/m2 on day 1 every 3 weeks), 16 for weekly topotecan (4 mg/m2 intravenously on days 1, 8 and 15 of a 28-day cycle). RESULTS: The median follow-up time was 12.45 months, there was no difference about disease control rates (DCR) between three chemotherapy regimens (DCR; 25.9% with irinotecan, 29.2% with CAV and 31.3% with topotecan, p=0.92). Objective response rates (ORR) for irinotecan, CAV and topotecan groups were 3,7%, 8,8%, and 0%, respectively (p=0.63). Median progression free survival (PFS) and overall survival (OS) were similar according to irinotecan, CAV, and topotecan (PFS: 1.93 months, 2.30 months and 3.45 months; OS: 2.89 months, 4.79 months and 5.81 months, respectively). The adverse events were generally mild and manageable for both hematological and nonhematological toxicities in all three arms. CONCLUSIONS: Weekly irinotecan, CAV and weekly topotecan are similarly effective and safe chemotherapy protocols for the treatment of CRR-SCLC patients.