The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) is a tyrosine kinase signaling pathway that has a fundamental role in many biologic processes including embryonic ...development, tissue regeneration, and angiogenesis. Increasing evidence indicates that this pathway plays a critical role in oncogenesis via gene amplification, activating mutations, or translocation in tumors of various histologies. With multiplex sequencing technology, the detection of FGFR aberrations has become more common and is tied to cancer cell proliferation, resistance to anticancer therapies, and neoangiogenesis. Inhibition of FGFR signaling appears promising in preclinical studies, suggesting a pathway of clinical interest in the development of targeted therapy. Phase I trials have demonstrated a manageable toxicity profile. Currently, there are multiple FGFR inhibitors under study with many non-selective (multi-kinase) inhibitors demonstrating limited clinical responses. As we progress from the first generation of non-selective drugs to the second generation of selective FGFR inhibitors, it is clear that FGFR aberrations do not behave uniformly across cancer types; thus, a deeper understanding of biomarker strategies is undoubtedly warranted. This review aims to consolidate data from recent clinical trials with a focus on selective FGFR inhibitors. As Phase II clinical trials emerge, concentration on patient selection as it pertains to predicting response to therapy, feasible methods for overcoming toxicity, and the likelihood of combination therapies should be utilized. We will also discuss qualities that may be desirable in future generations of FGFR inhibitors, with the hope that overcoming these current barriers will expedite the availability of this novel class of medications.
Learning Objectives
After completing this course, the reader will be able to:
Promptly recognize cardiovascular adverse events associated with anti‐VEGF therapy in order to formulate treatment plans ...to counteract them.
Explain possible mechanisms by which bevacizumab, sunitinib, and sorafenib lead to cardiovascular complications and develop strategies for managing these complications.
Describe the role of RAAS in vasoconstriction and capillary rarefaction and strategize the use of RAAS inhibition to manage these toxicities.
This article is available for continuing medical education credit at CME.TheOncologist.com
Background.
Therapies targeting vascular endothelial growth factor (VEGF) are associated with hypertension, cardiotoxicity, and thromboembolic events.
Methods.
All prospective phase I–III clinical trials published up to December 2008 of approved anti‐VEGF therapies (bevacizumab, sunitinib, sorafenib) and relevant literature were reviewed.
Results.
The rates of Common Toxicity Criteria (version 3) grade 3–4 hypertension with bevacizumab, sunitinib, and sorafenib were 9.2%, 6.9%, and 7.2%, respectively. Grade 3–4 left ventricular systolic dysfunction was noted in 0.3%, 1.4%, and 0.05% of patients, respectively, whereas the rates of grade 3–4 thromboembolism were 9.6%, 1.2%, and 3.8%, respectively. The renin–angiotensin–aldosterone system (RAAS) may play a key role in vasoconstriction and capillary rarefaction, which are unleashed when VEGF signaling is targeted. Inhibiting RAAS may be the optimal approach for managing these toxicities.
Conclusions.
In anticipation of cardiovascular complications with anti‐VEGF therapies, early detection and personalized management may improve clinical outcomes and tolerance.
This review focuses on the potential cardiovascular toxicities associated with the use of bevacizumab, sunitinib, and sorafenib in order to increase awareness about these complications and to discuss their clinical significance and therapeutic interventions.
Although transcript levels have been traditionally used as a surrogate measure of gene expression, it is increasingly recognized that the latter is extensively and dynamically modulated at the level ...of translation (messenger RNA to protein). Over the recent years, significant progress has been made in dissecting the complex posttranscriptional mechanisms that regulate gene expression. This advancement in knowledge came hand in hand with the progress made in the methodologies to study translation both at gene-specific as well as global genomic level. The majority of translational control is exerted at the level of initiation; nonetheless, protein synthesis can be modulated at the level of translation elongation, termination, and recycling. Sequence and structural elements and epitranscriptomic modifications of individual transcripts allow for dynamic gene-specific modulation of translation. Cancer cells usurp the regulatory mechanisms that govern translation to carry out translational programs that lead to the phenotypic hallmarks of cancer. Translation is a critical nexus in neoplastic transformation. Multiple oncogenes and signaling pathways that are activated, upregulated, or mutated in cancer converge on translation and their transformative impact "bottlenecks" at the level of translation. Moreover, this translational dysregulation allows cancer cells to adapt to a diverse array of stresses associated with a hostile microenviroment and antitumor therapies. All elements involved in the process of translation, from the transcriptional template, the components of the translational machinery, to the proteins that interact with the transcriptome, have been found to be qualitatively and/or quantitatively perturbed in cancer. This review discusses the regulatory mechanisms that govern translation in normal cells and how translation becomes dysregulated in cancer leading to the phenotypic hallmarks of malignancy. We also discuss how dysregulated mediators or components of translation can be utilized as biomarkers with potential diagnostic, prognostic, or predictive significance. Such biomarkers have the potential advantage of uniform applicability in the face of inherent tumor heterogeneity and deoxyribonucleic acid instability. As translation becomes increasingly recognized as a process gone awry in cancer and agents are developed to target it, the utility and significance of these potential biomarkers is expected to increase.
Models that recapitulate the complexity of human tumors are urgently needed to develop more effective cancer therapies. We report a bank of human patient-derived xenografts (PDXs) and matched ...organoid cultures from tumors that represent the greatest unmet need: endocrine-resistant, treatment-refractory and metastatic breast cancers. We leverage matched PDXs and PDX-derived organoids (PDxO) for drug screening that is feasible and cost-effective with in vivo validation. Moreover, we demonstrate the feasibility of using these models for precision oncology in real time with clinical care in a case of triple-negative breast cancer (TNBC) with early metastatic recurrence. Our results uncovered a Food and Drug Administration (FDA)-approved drug with high efficacy against the models. Treatment with this therapy resulted in a complete response for the individual and a progression-free survival (PFS) period more than three times longer than their previous therapies. This work provides valuable methods and resources for functional precision medicine and drug development for human breast cancer.
Poly (ADP-ribose)-polymerase inhibitors (PARPi) have been approved for cancer patients with germline BRCA1/2 (gBRCA1/2) mutations, and efforts to expand the utility of PARPi beyond BRCA1/2 are ...ongoing. In preclinical models of triple-negative breast cancer (TNBC) with intact DNA repair, we have previously shown an induced synthetic lethality with combined EGFR inhibition and PARPi. Here, we report the safety and clinical activity of lapatinib and veliparib in patients with metastatic TNBC.
A first-in-human, pilot study of lapatinib and veliparib was conducted in metastatic TNBC (NCT02158507). The primary endpoint was safety and tolerability. Secondary endpoints were objective response rates and pharmacokinetic evaluation. Gene expression analysis of pre-treatment tumor biopsies was performed. Key eligibility included TNBC patients with measurable disease and prior anthracycline-based and taxane chemotherapy. Patients with gBRCA1/2 mutations were excluded.
Twenty patients were enrolled, of which 17 were evaluable for response. The median number of prior therapies in the metastatic setting was 1 (range 0-2). Fifty percent of patients were Caucasian, 45% African-American, and 5% Hispanic. Of evaluable patients, 4 demonstrated a partial response and 2 had stable disease. There were no dose-limiting toxicities. Most AEs were limited to grade 1 or 2 and no drug-drug interactions noted. Exploratory gene expression analysis suggested baseline DNA repair pathway score was lower and baseline immunogenicity was higher in the responders compared to non-responders.
Lapatinib plus veliparib therapy has a manageable safety profile and promising antitumor activity in advanced TNBC. Further investigation of dual therapy with EGFR inhibition and PARP inhibition is needed.
ClinicalTrials.gov , NCT02158507 . Registered on 12 September 2014.
Circulating tumor cells (CTC) are prognostic in metastatic breast cancer (MBC). We tested whether EpCAM-based capture system (CellSearch) is effective in patients with triple-negative (TN) MBC, and ...whether CTC apoptosis and clustering enhances the prognostic role of CTC.
CTC enumeration and apoptosis were determined using the CXC CellSearch kit at baseline and days 15 and 29 in blood drawn from TN MBC patients who participated in a prospective randomized phase II trial of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) with or without tigatuzumab. Association between levels of CTC and patient outcomes was assessed using logistic regression, Kaplan-Meier curves, and Cox proportional hazards modeling.
Nineteen of 52 (36.5%), 14 of 52 (26.9%), and 13 of 49 (26.5%) patients who were evaluable had elevated CTC (≥5 CTC/7.5 mL whole blood) at baseline and at days 15 and 29, respectively. Patients with elevated versus not elevated CTC at each time point had worse progression-free survival (PFS; P = 0.005, 0.0003, 0.0002, respectively). The odds of clinical benefit response for those who had elevated versus low CTC at baseline and days 15 and 29 were 0.25 (95% CI: 0.08-0.84; P = 0.024), 0.19 (95% CI: 0.05-0.17; P = 0.014), and 0.06 (95% CI: 0.01-0.33; P = 0.001), respectively. There was no apparent prognostic effect comparing CTC apoptosis versus non-apoptosis. Presence of CTC cluster at day 15 and day 29 was associated with shorter PFS.
CTC were detected using CellSearch assay in approximately one-third of TN MBC patients. Elevated CTC at baseline and days 15 and 29 were prognostic, and reductions in CTC levels reflected response.
Type 1 diabetes mellitus (T1DM) is a rare, but serious immune-related adverse event (irAE) of immune checkpoint inhibitors (ICIs). Our goal was to characterize treatment outcomes associated with ...ICI-induced T1DM through analysis of clinical, immunological and proteomic data.
This was a single-center case series of patients with solid tumors who received ICIs and subsequently had a new diagnosis of T1DM. ICD codes and C-peptide levels were used to identify patients for chart review to confirm ICI-induced T1DM. Baseline blood specimens were studied for proteomic and immunophenotypic changes.
Between 2011 and 2023, 18 of 3744 patients treated at Huntsman Cancer Institute with ICIs were confirmed to have ICI-induced T1DM (0.48%). Eleven of the 18 patients received anti-PD1 monotherapy, 4 received anti-PD1 plus chemotherapy or targeted therapy, and 3 received ipilimumab plus nivolumab. The mean time to onset was 218 days (range 22-418 days). Patients had sudden elevated serum glucose within 2-3 weeks prior to diagnosis. Sixteen (89%) presented with diabetic ketoacidosis. Three of 12 patients had positive T1DM-associated autoantibodies. All patients with T1DM became insulin-dependent through follow-up. At median follow-up of 21.9 months (range 8.4-82.4), no patients in the melanoma group had progressed or died from disease. In the melanoma group, best responses were 2 complete response and 2 partial response while on active treatment; none in the adjuvant group had disease recurrence. Proteomic analysis of baseline blood suggested low inflammatory (IL-6, OSMR) markers and high metabolic (GLO1, DXCR) markers in ICI-induced T1DM cohort.
Our case series demonstrates rapid onset and irreversibility of ICI-induced T1DM. Melanoma patients with ICI-induced T1DM display excellent clinical response and survival. Limited proteomic data also suggested a unique proteomic profile. Our study helps clinicians to understand the unique clinical presentation and long-term outcomes of this rare irAE for best clinical management.
Objective To assess the relationship between time-of-day of exercise training and changes in relevant cancer health outcomes among cancer survivors. Methods Retrospective analysis of data collected ...from 2016-2019 from a hospital-based exercise oncology program. Descriptive statistics were calculated for demographic, clinical, and exercise timing characteristics (e.g. AM, PM, or mix) among survivors with available data for exercise training time (n = 233). For the total sample and a breast cancer sub-analysis, univariate analysis of covariance, adjusted for age, was carried out by exercise training time, for change in the following outcomes collected during the program's assessment sessions: cardiorespiratory fitness and muscular endurance (human performance variables), physical function, anthropometrics, self-reported fatigue, and quality of life (QoL). Change in body mass index (BMI) and body weight was included in the breast cancer analysis. Results Overall, 37.3% of survivors habitually engaged in AM exercise (e.g. greater than or equal to 75% AM training), 34.3% in PM exercise, and 28.3% in a mix of AM and PM exercise training throughout the program. Median time in the program was 17 weeks. Significant improvements in most human performance and physical function variables were observed in the total sample regardless of exercise training time-of-day. Among breast cancer survivors, PM but not AM or mixed was associated with improvements in fitness, and lower-body muscular endurance and function. Mixed exercise timing was linked with greater increase in waist circumference (total sample: 3.02cm, 95%CI 1.55, 4.49; breast cancer: 3.57cm 95%CI 0.96, 6.18), body weight (breast cancer: 1.6kg, 95%CI 0.3, 2.8) and BMI (breast cancer: 0.6kg/m.sup.2, 95%CI 0.1, 1.0). AM and PM exercise, but not mixed, was associated with improvements in fatigue and QoL. Conclusion Time-of-day of exercise training may differentially impact changes in human performance and physical function variables. Mixed exercise training time may result in less favorable outcomes related of weight management variables among cancer survivors.
Gene expression is extensively and dynamically modulated at the level of translation. How cancer cells prioritize the translation of certain mRNAs over others from a pool of competing mRNAs remains ...an open question. Here, we analyze translation in cell line models of breast cancer and normal mammary tissue by ribosome profiling. We identify key recurrent themes of oncogenic translation: higher ribosome occupancy, greater variance of translational efficiencies, and preferential translation of transcriptional regulators and signaling proteins in malignant cells as compared with their nonmalignant counterpart. We survey for candidate RNA interacting proteins that could associate with the 5′untranslated regions of the transcripts preferentially translated in breast tumour cells. We identify SRSF1, a prototypic splicing factor, to have a pervasive direct and indirect impact on translation. In a representative estrogen receptor–positive and estrogen receptor–negative cell line, we find that protein synthesis relies heavily on SRSF1. SRSF1 is predominantly intranuclear. Under certain conditions, SRSF1 translocates from the nucleus to the cytoplasm where it associates with MYC and CDK1 mRNAs and upregulates their internal ribosome entry site–mediated translation. Our results point to a synergy between splicing and translation and unveil how certain RNA-binding proteins modulate the translational landscape in breast cancer.
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