Clinical characteristics and treatment patterns of patients with NTRK fusion-positive solid tumors: A multisite cohort study at US academic cancer centers.

BACKGROUND: Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are rare oncogenic drivers prevalent in 0.3% of solid tumors. They are most common in salivary gland cancer (2.6%), thyroid cancer (1.6%), and soft-tissue sarcoma (1.5%). Currently, there are 2 US Food and Drug Administration-approved targeted therapies for NTRK gene fusions: larotrectinib, approved in 2018, and entrectinib, approved in 2019. To date, the real-world uptake of tyrosine receptor kinase inhibitor (TRKi) use for NTRK-positive solid tumors in academic cancer centers remains largely unknown. OBJECTIVE: To describe the demographics, clinical and genomic characteristics, and testing and treatment patterns of patients with NTRK-positive solid tumors treated at US academic cancer centers. METHODS: This was a retrospective chart review study conducted in academic cancer centers in the United States. All patients diagnosed with an NTRK fusion-positive (NTRK1, NTRK2, NTRK3) solid tumor (any stage) and who received cancer treatment at participating sites between January 1, 2012, and July 1, 2023, were included in this study. Patient demographics, clinical characteristics, genomic characteristics, NTRK testing data, and treatment patterns were collected from electronic medical records and analyzed using descriptive statistics as appropriate. RESULTS: In total, 6 centers contributed data for 55 patients with NTRK-positive tumors. The mean age was 49.3 (SD = 20.5) years, 51% patients were female, and the majority were White (78%). The median duration of time from cancer diagnosis to NTRK testing was 85 days (IQR = 44-978). At the time of NTRK testing, 64% of patients had stage IV disease, compared with 33% at cancer diagnosis. Prevalent cancer types in the overall cohort included head and neck (15%), thyroid (15%), brain (13%), lung (13%), and colorectal (11%). NTRK1 fusions were most common (45%), followed by NTRK3 (40%) and NTRK2 (15%). Across all lines of therapy, 51% of patients (n = 28) received a TRKi. Among TRKi-treated patients, 71% had stage IV disease at TRKi initiation. The median time from positive NTRK test to initiation of TRKi was 48 days (IQR = 9-207). TRKis were commonly given as first-line (30%) or second-line (48%) therapies. Median duration of therapy was 610 (IQR = 182-764) days for TRKi use and 207.5 (IQR = 42-539) days for all other first-line therapies. CONCLUSIONS: This study reports on contemporary real-world NTRK testing patterns and use of TRKis in solid tumors, including time between NTRK testing and initiation of TRKi therapy and duration of TRKi therapy.

Emerging Therapeutic Strategies to Overcome Drug Resistance in Cancer Cells.

The rise of drug resistance in cancer cells presents a formidable challenge in modern oncology, necessitating the exploration of innovative therapeutic strategies. This review investigates the latest advancements in overcoming drug resistance mechanisms employed by cancer cells, focusing on emerging therapeutic modalities. The intricate molecular insights into drug resistance, including genetic mutations, efflux pumps, altered signaling pathways, and microenvironmental influences, are discussed. Furthermore, the promising avenues offered by targeted therapies, combination treatments, immunotherapies, and precision medicine approaches are highlighted. Specifically, the synergistic effects of combining traditional cytotoxic agents with molecularly targeted inhibitors to circumvent resistance pathways are examined. Additionally, the evolving landscape of immunotherapeutic interventions, including immune checkpoint inhibitors and adoptive cell therapies, is explored in terms of bolstering anti-tumor immune responses and overcoming immune evasion mechanisms. Moreover, the significance of biomarker-driven strategies for predicting and monitoring treatment responses is underscored, thereby optimizing therapeutic outcomes. For insights into the future direction of cancer treatment paradigms, the current review focused on prevailing drug resistance challenges and improving patient outcomes, through an integrative analysis of these emerging therapeutic strategies.

Teriflunomide/leflunomide synergize with chemotherapeutics by decreasing mitochondrial fragmentation via DRP1 in SCLC.

Although up to 80% small cell lung cancer (SCLC) patients' response is good for first-line chemotherapy regimen, most patients develop recurrence of the disease within weeks to months. Here, we report cytostatic effect of leflunomide (Leflu) and teriflunomide (Teri) on SCLC cell proliferation through inhibition of DRP1 phosphorylation at Ser616 and decreased mitochondrial fragmentation. When administered together, Teri and carboplatin (Carbo) act synergistically to significantly inhibit cell proliferation and DRP1 phosphorylation, reduce abundance of intermediates in pyrimidine de novo pathway, and increase apoptosis and DNA damage. Combination of Leflu&Carbo has anti-tumorigenic effect in vivo. Additionally, lurbinectedin (Lur) and Teri potently and synergistically inhibited spheroid growth and depleted uridine and DRP1 phosphorylation in mouse tumors. Our results suggest combinations of Carbo and Lur with Teri or Leflu are efficacious and underscore how the relationship between DRP1/DHODH and mitochondrial plasticity serves as a potential therapeutic target to validate these treatment strategies in SCLC clinical trials.

Leveraging Cancer Phenotypic Plasticity for Novel Treatment Strategies.

Cancer cells, like all other organisms, are adept at switching their phenotype to adjust to the changes in their environment. Thus, phenotypic plasticity is a quantitative trait that confers a fitness advantage to the cancer cell by altering its phenotype to suit environmental circumstances. Until recently, new traits, especially in cancer, were thought to arise due to genetic factors; however, it is now amply evident that such traits could also emerge non-genetically due to phenotypic plasticity. Furthermore, phenotypic plasticity of cancer cells contributes to phenotypic heterogeneity in the population, which is a major impediment in treating the disease. Finally, plasticity also impacts the group behavior of cancer cells, since competition and cooperation among multiple clonal groups within the population and the interactions they have with the tumor microenvironment also contribute to the evolution of drug resistance. Thus, understanding the mechanisms that cancer cells exploit to tailor their phenotypes at a systems level can aid the development of novel cancer therapeutics and treatment strategies. Here, we present our perspective on a team medicine-based approach to gain a deeper understanding of the phenomenon to develop new therapeutic strategies.

Management of KRAS-mutated non-small cell lung cancer.

Kirsten rat sarcoma virus (KRAS) is the most frequently mutated oncogene in human cancers, particularly in non-small cell lung cancer (NSCLC), where mutations are present in 32% of lung adenocarcinoma and 4% of squamous cell lung cancer. The most common KRAS variant is KRAS G12C, which accounts for nearly 40% of all KRAS mutations. Although it is the most common oncogenic driver in NSCLC, KRAS was considered a "nondruggable target" until recently, owing to the lack of any progress in developing targeted therapies for this oncogene. With the recent development and approval of selective KRAS G12C inhibitors such as sotorasib and adagrasib for the treatment of advanced or metastatic NSCLC in the second-line setting and beyond, the standard of care for managing these tumors has undergone a significant change. Mechanisms of resistance to KRAS G12C inhibitors are highly heterogeneous, including both on-target and off-target resistance as well as morphologic switching, thus limiting the activity of these drugs when used as monotherapy. New-generation inhibitors and different combination strategies are being developed in early-phase trials to overcome or delay the onset of resistance as well as to target non-G12C mutations. Owing to the biological heterogeneity of KRAS-mutant NSCLC, treatment will likely need to be individualized based on factors such as co-occurring mutations.

Increase in Full-Length Dystrophin by Exon Skipping in Duchenne Muscular Dystrophy Patients with Single Exon Duplications: An Open-label Study.

Single exon duplications account for disease in a minority of Duchenne muscular dystrophy patients. Exon skipping in these patients has the potential to be highly therapeutic through restoration of full-length dystrophin expression. We conducted a 48-week open label study of casimersen and golodirsen in 3 subjects with an exon 45 or 53 duplication. Two subjects (aged 18 and 23 years) were non-ambulatory at baseline. Upper limb, pulmonary, and cardiac function appeared stable in the 2 subjects in whom they could be evaluated. Dystrophin expression increased from 0.94 % ±0.59% (mean±SD) of normal to 5.1% ±2.9% by western blot. Percent dystrophin positive fibers also rose from 14% ±17% at baseline to 50% ±42% . Our results provide initial evidence that the use of exon-skipping drugs may increase dystrophin levels in patients with single-exon duplications.

Efficacy and safety of anti-programmed cell death protein 1 antibody combination therapy in patients with advanced experienced epidermal growth factor receptor-tyrosine kinase inhibitor-resistant lung adenocarcinoma: a retrospective cohort study.

Background: The effectiveness of combining anti-programmed cell death protein 1 (PD-1) and chemotherapy has been evaluated as superior to that of chemotherapy alone in the patients with advanced epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)-resistant non-small cell lung cancer (NSCLC). In this study the efficacy and safety of anti-PD-1 combination therapy were evaluated retrospectively in patients who experienced EGFR-TKI-resistant with advanced lung adenocarcinoma (LUAD), with the goal of providing helpful guidance for clinical application. Methods: The clinical results of patients with incurable LUAD who received anti-PD-1 antibody combined with or without anti-angiogenic or chemotherapy after EGFR-TKI therapy failure were collected. The efficacy was calculated based on the objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). The efficacy of the regimes was compared according to treatment groups and programmed cell death ligand 1 (PD-L1) expression. Results: The final analysis included a total of 43 patients with advanced EGFR-mutant LUAD. The overall cohort had an ORR of 23.3%, median PFS (mPFS) of 6.5 months, and median OS (mOS) of 10.6 months. No notable distinction was observed in mPFS and mOS among patients receiving three types of anti-PD-1 antibody combination therapies. Patients with positive PD-L1 expression showed a longer mPFS compared to patients with negative PD-L1 expression. No statistical difference was detected in terms of mPFS between the use of immune combination chemotherapy and immune combination anti-angiogenic therapy in the PD-L1 positive subgroup, and PFS was prolonged regardless of the PD-L1 expression status being positive or negative in the population receiving immune combination chemotherapy. Treatment-related adverse events (TRAEs) of grade 3 or higher were observed in 16.3% of patients, including chemotherapy-containing immunotherapy. No deaths resulting from immune-related adverse events (irAEs) were reported, and only 1 patient receiving immunotherapy plus chemotherapy had to discontinue treatment due to irAEs. Conclusions: Combination immunotherapy is feasible in post-TKI resistant individuals with LUAD harboring EGFR mutations. Immune combination chemotherapy and immune combination anti-angiogenic therapy have equivalent efficacy in the PD-L1 positive population. PD-L1 expression can be used as a reference for screening candidates for combination immunotherapy.

A Nexus between Genetic and Non-Genetic Mechanisms Guides KRAS Inhibitor Resistance in Lung Cancer.

Several studies in the last few years have determined that, in contrast to the prevailing dogma that drug resistance is simply due to Darwinian evolution-the selection of mutant clones in response to drug treatment-non-genetic changes can also lead to drug resistance whereby tolerant, reversible phenotypes are eventually relinquished by resistant, irreversible phenotypes. Here, using KRAS as a paradigm, we illustrate how this nexus between genetic and non-genetic mechanisms enables cancer cells to evade the harmful effects of drug treatment. We discuss how the conformational dynamics of the KRAS molecule, that includes intrinsically disordered regions, is influenced by the binding of the targeted therapies contributing to conformational noise and how this noise impacts the interaction of KRAS with partner proteins to rewire the protein interaction network. Thus, in response to drug treatment, reversible drug-tolerant phenotypes emerge via non-genetic mechanisms that eventually enable the emergence of irreversible resistant clones via genetic mutations. Furthermore, we also discuss the recent data demonstrating how combination therapy can help alleviate KRAS drug resistance in lung cancer, and how new treatment strategies based on evolutionary principles may help minimize or even preclude the emergence of drug resistance.

Delandistrogene Moxeparvovec Gene Therapy in Ambulatory Patients (Aged ≥4 to <8 Years) with Duchenne Muscular Dystrophy: 1-Year Interim Results from Study SRP-9001-103 (ENDEAVOR).

OBJECTIVE: Delandistrogene moxeparvovec is approved in the USA for the treatment of ambulatory patients (4-5 years) with Duchenne muscular dystrophy. ENDEAVOR (SRP-9001-103; NCT04626674) is a single-arm, open-label study to evaluate delandistrogene moxeparvovec micro-dystrophin expression, safety, and functional outcomes following administration of commercial process delandistrogene moxeparvovec. METHODS: In cohort 1 of ENDEAVOR (N = 20), eligible ambulatory males, aged ≥4 to <8 years, received a single intravenous infusion of delandistrogene moxeparvovec (1.33 × 1014 vg/kg). The primary endpoint was change from baseline (CFBL) to week 12 in delandistrogene moxeparvovec micro-dystrophin by western blot. Additional endpoints evaluated included: safety; vector genome copies; CFBL to week 12 in muscle fiber-localized micro-dystrophin by immunofluorescence; and functional assessments, including North Star Ambulatory Assessment, with comparison with a propensity score-weighted external natural history control. RESULTS: The 1-year safety profile of commercial process delandistrogene moxeparvovec in ENDEAVOR was consistent with safety data reported in other delandistrogene moxeparvovec trials (NCT03375164 and NCT03769116). Delandistrogene moxeparvovec micro-dystrophin expression was robust, with sarcolemmal localization at week 12; mean (SD) CFBL in western blot, 54.2% (42.6); p < 0.0001. At 1 year, patients demonstrated stabilized or improved North Star Ambulatory Assessment total scores; mean (SD) CFBL, +4.0 (3.5). Treatment versus a propensity score-weighted external natural history control demonstrated a statistically significant difference in least squares mean (standard error) CFBL in North Star Ambulatory Assessment, +3.2 (0.6) points; p < 0.0001. INTERPRETATION: Results confirm efficient transduction of muscle by delandistrogene moxeparvovec. One-year post-treatment, delandistrogene moxeparvovec was well tolerated, and demonstrated stabilized or improved motor function, suggesting a clinical benefit for patients with Duchenne muscular dystrophy. ANN NEUROL 2023;94:955-968.

Pneumonitis in advanced non-small cell lung cancer: no interaction between immune checkpoint inhibition and radiation therapy.

Background: Radiation pneumonitis and immune-related pneumonitis have been studied independently, but little information has emerged on the interactions between radiation therapy (RT) and immune checkpoint inhibition (ICI). We examine whether RT and ICI are synergistic in causing pneumonitis. Methods: A retrospective cohort was assembled using the Surveillance, Epidemiology, and End Results-Medicare database, including Medicare beneficiaries diagnosed with American Joint Committee on Cancer 7th ed. (AJCC) stages IIIB-IV NSCLC between 2013-2017. Exposures to RT and ICI were determined by evaluating for treatment within 12 months of diagnosis (RT group and ICI group) and for a second exposure (e.g., ICI after RT) within 3 months after the first exposure (RT + ICI group). Untreated controls were matched to treated patients who were diagnosed in the same three-month window. A validated algorithm for identifying cases of pneumonitis in claims data was used to evaluate for the outcome within 6 months after treatment. The primary outcome was the relative excess risk due to interaction (RERI), a quantitative measure of additive interaction between two treatments. Results: There were 18,780 patients included in the analysis with 9,345 (49.8%), 7,533 (40.2%), 1,332 (7.1%), and 550 (2.9%) in the control, RT, ICI, and RT + ICI groups, respectively. Relative to controls, the hazards ratios of pneumonitis were 11.5 (95% CI: 7.9 to 17.0), 6.2 (95% CI: 3.8 to 10.3), and 10.7 (95% CI: 6.0 to 19.2) in the RT, ICI, and RT-ICI groups, respectively. The RERIs were -6.1 (95% CI: -13.1 to -0.6, P=0.97) and -4.0 (95% CI: -10.7 to 1.5, P=0.91) in the unadjusted and adjusted analyses, respectively, consistent with no evidence of additive interaction (RERI ≤0) between RT and ICI. Conclusions: In this study of Medicare beneficiaries with advanced NSCLC, RT and ICI were, at most, additive rather than synergistic in causing pneumonitis. Pneumonitis risk in patients treated with RT and ICI is not more than could be expected from each therapy alone.

MyoD-induced reprogramming of human fibroblasts and urinary stem cells in vitro: protocols and their applications.

The conversion of fibroblasts into myogenic cells is a powerful tool to both develop and test therapeutic strategies and to perform in-depth investigations of neuromuscular disorders, avoiding the need for muscle biopsies. We developed an easy, reproducible, and high-efficiency lentivirus-mediated transdifferentiation protocol, that can be used to convert healthy donor fibroblasts and a promising new cellular model, urinary stem cells (USCs), into myoblasts, that can be further differentiated into multinucleated myotubes in vitro. Transcriptome and proteome profiling of specific muscle markers (desmin, myosin, dystrophin) was performed to characterize both the myoblasts and myotubes derived from each cell type and to test the transdifferentiation-inducing capacity of MYOD1 in fibroblasts and USCs. Specifically, the Duchenne muscular dystrophy (DMD) transcripts and proteins, including both the full-length Dp427 and the short Dp71 isoform, were evaluated. The protocol was firstly developed in healthy donor fibroblasts and USCs and then used to convert DMD patients' fibroblasts, with the aim of testing the efficacy of an antisense drug in vitro. Technical issues, limitations, and problems are explained and discussed. We demonstrate that MyoD-induced-fibroblasts and USCs are a useful in vitro model of myogenic cells to investigate possible therapies for neuromuscular diseases.

Integrating Early-Stage Drug Development with Clinical Networks; Challenges and Opportunities: The City of Hope Developing Experience.

Recent data suggest that patients with advanced cancer who participate in biomarker/genomically informed early-stage clinical trials experience clinical benefit. While most early-stage clinical trials are conducted in major academic centers, the majority of cancer patients in the United States are treated in community practices. Here, we describe ongoing efforts at the City of Hope Cancer Center to integrate our network community oncology clinical practices into our academic, centralized biomarker/genomic-driven, early-stage clinical trial program to build an understanding of the approaches that provide the benefits of early-stage clinical trial participation to community patients. Our efforts include three key initiatives: the development of a virtual "Refractory Disease" phase 1 trial matching televideo clinic, the construction of infrastructure to support the expansion of phase 1 clinical trials to a distant regional clinical satellite hub, and the implementation of an enterprise-wide precision medicine, germline, and somatic testing program. Our work at City of Hope may serve as an example to facilitate similar efforts at other institutions.

A phase I trial of riluzole and sorafenib in patients with advanced solid tumors: CTEP #8850.

BACKGROUND: Overexpression of metabotropic glutamate receptor 1 (GRM1) has been implicated in the pathogenesis of multiple cancers. Riluzole, an inhibitor of glutamate release, showed synergistic antitumor activity in combination with the multi-kinase inhibitor sorafenib in preclinical models. This phase I trial identified the toxicity profile, dose-limiting toxicities, maximum tolerated dose (MTD), and pharmacokinetic and pharmacodynamic properties of riluzole combined with sorafenib in patients with advanced cancers. PATIENTS AND METHODS: Patients with refractory solid tumors were enrolled utilizing a 3+3 dose-escalation design. Riluzole was given at 100 mg PO BID in combination with sorafenib, beginning at 200 mg PO daily and escalating in 200 mg increments per level in 28-day cycles. Restaging evaluations were performed every 2 cycles. RESULTS: 35 patients were enrolled over 4 dose levels. The MTD was declared at dose level 3 (riluzole: 100 mg PO BID; sorafenib: 400 mg AM/200 mg PM). Pharmacokinetic analyses did not reveal definitive evidence of drug-drug interactions. Consistent decreases in phospho-forms of ERK and AKT in tumor tissue analyses with accompanying decrease in GRM1 expression and increase in pro-apoptotic BIM suggest target engagement by the combination. Best responses included a partial response in 1 (2.9%) patient with pancreatic acinar cell carcinoma with a KANK4-RAF1 fusion, and stable disease in 11 (36%) patients. CONCLUSION: Combination therapy with riluzole and sorafenib was safe and tolerable in patients with advanced solid tumors. The partial response in a patient with a RAF1 fusion suggests that further exploration in a genomically selected cohort may be warranted.

A Systems Biology Approach for Addressing Cisplatin Resistance in Non-Small Cell Lung Cancer.

Translational research in medicine, defined as the transfer of knowledge and discovery from the basic sciences to the clinic, is typically achieved through interactions between members across scientific disciplines to overcome the traditional silos within the community. Thus, translational medicine underscores 'Team Medicine', the partnership between basic science researchers and clinicians focused on addressing a specific goal in medicine. Here, we highlight this concept from a City of Hope perspective. Using cisplatin resistance in non-small cell lung cancer (NSCLC) as a paradigm, we describe how basic research scientists, clinical research scientists, and medical oncologists, in true 'Team Science' spirit, addressed cisplatin resistance in NSCLC and identified a previously approved compound that is able to alleviate cisplatin resistance in NSCLC. Furthermore, we discuss how a 'Team Medicine' approach can help to elucidate the mechanisms of innate and acquired resistance in NSCLC and develop alternative strategies to overcome drug resistance.

Inhibition of autophagy and MEK promotes ferroptosis in Lkb1-deficient Kras-driven lung tumors.

LKB1 and KRAS are the third most frequent co-mutations detected in non-small cell lung cancer (NSCLC) and cause aggressive tumor growth. Unfortunately, treatment with RAS-RAF-MEK-ERK pathway inhibitors has minimal therapeutic efficacy in LKB1-mutant KRAS-driven NSCLC. Autophagy, an intracellular nutrient scavenging pathway, compensates for Lkb1 loss to support Kras-driven lung tumor growth. Here we preclinically evaluate the possibility of autophagy inhibition together with MEK inhibition as a treatment for Kras-driven lung tumors. We found that the combination of the autophagy inhibitor hydroxychloroquine (HCQ) and the MEK inhibitor Trametinib displays synergistic anti-proliferative activity in KrasG12D/+;Lkb1-/- (KL) lung cancer cells, but not in KrasG12D/+;p53-/- (KP) lung cancer cells. In vivo studies using tumor allografts, genetically engineered mouse models (GEMMs) and patient-derived xenografts (PDXs) showed anti-tumor activity of the combination of HCQ and Trametinib on KL but not KP tumors. We further found that the combination treatment significantly reduced mitochondrial membrane potential, basal respiration, and ATP production, while also increasing lipid peroxidation, indicative of ferroptosis, in KL tumor-derived cell lines (TDCLs) and KL tumors compared to treatment with single agents. Moreover, the reduced tumor growth by the combination treatment was rescued by ferroptosis inhibitor. Taken together, we demonstrate that autophagy upregulation in KL tumors causes resistance to Trametinib by inhibiting ferroptosis. Therefore, a combination of autophagy and MEK inhibition could be a novel therapeutic strategy to specifically treat NSCLC bearing co-mutations of LKB1 and KRAS.

Racial disparities in follow-up care of early-stage lung cancer survivors.

PURPOSE: To investigate if race impacts receipt of follow-up care in lung cancer survivors, we conducted a cross-sectional study in lung cancer survivors recruited through the New Jersey State Cancer Registry (NJSCR). METHODS: Between May 2019 and December 2019, survivors of early-stage NSCLC were identified and recruited from the NJSCR. Eligible participants were asked to complete a paper survey questionnaire and medical record release form sent to them by mail. RESULTS: Of the 112 survivors included in the analysis, 78 (70%) were non-Hispanic (NH) Whites and 34 (30%) were NH Blacks. Mean age was 67 years, 61% were female, and 92% had cancer in remission. A total of 82% of participants reported receiving a surveillance scan (CT or PET) within 1 year of completing the study survey. More NH White survivors received a scan within a year compared to NH Black survivors (89% vs 70%; p = 0.02). More NH White survivors (94%) reported that they were informed of the need for follow-up care by their provider compared to NH Blacks (71%; p = 0.002). Only 57% survivors reported receiving a treatment summary. Significant barriers to care were out-of-pocket costs (24%), non-coverage of test (12.5%), and lack of insurance (10%). CONCLUSIONS: Significant disparity was identified between NH Blacks and NH Whites in receipt of surveillance scans, as well as in receiving information about need for follow-up care. Low income, lack of insurance, and other financial concerns were identified as significant barriers to follow-up care. IMPLICATIONS FOR CANCER SURVIVORS: Future interventions to increase survivorship care should target specific unmet needs identified in each survivor population.

Oncolytic Viruses and Cancer Immunotherapy.

PURPOSE OF REVIEW: Oncolytic viruses (OVs) exert their antitumor effect through selective killing of cancer cells and induction of host anti-tumor immunity. This review aims to summarize the recent and current trials with OVs for the treatment of lung cancer. RECENT FINDINGS: Several OVs have been developed for the treatment of lung cancer including adenovirus, coxsackievirus B3, reovirus, and vaccinia virus and trials have demonstrated a safe toxicity profile. Early-phase trials in lung cancer with OVs have reported antiviral immune responses and evidence of clinical benefit. However, clinical efficacy of OVs in lung cancer either as monotherapy or in combination with chemotherapy has not been confirmed in larger phase II or III trials. Development of OVs in lung cancer has been limited by difficulty in administering OVs in the tumor directly as well as achieving adequate viral load at all tumor sites with systemically administered OVs. Developing novel combinations with OVs, especially checkpoint inhibitors and other immunotherapeutics, may be a strategy to address the limited success seen thus far. Integrating appropriate biomarker studies and meaningful endpoints in future clinical trials will be imperative. Using novel viral delivery systems in addition to increasing tumor specificity through improved genetic modifications in the OVs are other strategies to improve efficacy.

Smoothened percentiles for height, weight and body mass index of urban school going adolescents aged 11-17 years in national capital territory region of Delhi, India.

Purpose: The aim of the study was to estimate centiles by using improved statistical smoothing procedure, the Box-Cox power-exponential (BCPE) method, in urban northern Indian adolescents aged 11-17 years. Materials and Methods: Data were collected cross-sectionally by measuring specific anthropometric features such as height, weight, and mid-upper arm circumference in school-based adolescents aged 11-17 years including both boys (n = 838) and girls (n = 788) enrolled in government educational institutions in urban Delhi. We used a state-of-the-art statistical methodology (BCPE method) to establish centile curves. Results: The model fitted before smoothing revealed that weight, height, and BMI did not follow a normal distribution; both skewness and kurtosis were observed in all three variables. After correcting both skewness and kurtosis, estimated empirical percentile values showed a gradual increase in weight, height, and BMI in both boys and girls. Girls had higher weight and height than boys in initial ages and observed a steep increase in boys in both weight and height in later ages. BMI was higher in girls than boys and visibly higher during 14-16 years of age. The 50th percentile value of BMI was smaller in all the ages in our study than that in other studies. Conclusions: Smoothened percentile values derived for BMI by using the state-of-the-art statistical methodology may help policymakers to promote better growth in urban adolescents.

Ectopic clotting factor VIII expression and misfolding in hepatocytes as a cause for hepatocellular carcinoma.

Hemophilia A gene therapy targets hepatocytes to express B domain deleted (BDD) clotting factor VIII (FVIII) to permit viral encapsidation. Since BDD is prone to misfolding in the endoplasmic reticulum (ER) and ER protein misfolding in hepatocytes followed by high-fat diet (HFD) can cause hepatocellular carcinoma (HCC), we studied how FVIII misfolding impacts HCC development using hepatocyte DNA delivery to express three proteins from the same parental vector: (1) well-folded cytosolic dihydrofolate reductase (DHFR); (2) BDD-FVIII, which is prone to misfolding in the ER; and (3) N6-FVIII, which folds more efficiently than BDD-FVIII. One week after DNA delivery, when FVIII expression was undetectable, mice were fed HFD for 65 weeks. Remarkably, all mice that received BDD-FVIII vector developed liver tumors, whereas only 58% of mice that received N6 and no mice that received DHFR vector developed liver tumors, suggesting that the degree of protein misfolding in the ER increases predisposition to HCC in the context of an HFD and in the absence of viral transduction. Our findings raise concerns of ectopic BDD-FVIII expression in hepatocytes in the clinic, which poses risks independent of viral vector integration. Limited expression per hepatocyte and/or use of proteins that avoid misfolding may enhance safety.

Addressing Drug Resistance in Cancer: A Team Medicine Approach.

Drug resistance remains one of the major impediments to treating cancer. Although many patients respond well initially, resistance to therapy typically ensues. Several confounding factors appear to contribute to this challenge. Here, we first discuss some of the challenges associated with drug resistance. We then discuss how a 'Team Medicine' approach, involving an interdisciplinary team of basic scientists working together with clinicians, has uncovered new therapeutic strategies. These strategies, referred to as intermittent or 'adaptive' therapy, which are based on eco-evolutionary principles, have met with remarkable success in potentially precluding or delaying the emergence of drug resistance in several cancers. Incorporating such treatment strategies into clinical protocols could potentially enhance the precision of delivering personalized medicine to patients. Furthermore, reaching out to patients in the network of hospitals affiliated with leading academic centers could help them benefit from such innovative treatment options. Finally, lowering the dose of the drug and its frequency (because of intermittent rather than continuous therapy) can also have a significant impact on lowering the toxicity and undesirable side effects of the drugs while lowering the financial burden carried by the patient and insurance providers.