Resistance to Antibody-Drug Conjugates García-Alonso, Sara; Ocaña, Alberto; Pandiella, Atanasio
Cancer research (Chicago, Ill.),
05/2018, Letnik:
78, Številka:
9
Journal Article
Recenzirano
Antibody-drug conjugates (ADC) are multicomponent molecules constituted by an antibody covalently linked to a potent cytotoxic agent. ADCs combine high target specificity provided by the antibody ...together with strong antitumoral properties provided by the attached cytotoxic agent. At present, four ADCs have been approved and over 60 are being explored in clinical trials. Despite their effectiveness, resistance to these drugs unfortunately occurs. Efforts to understand the bases underlying such resistance are being carried out with the final purpose of counteracting them. In this review, we report described mechanisms of resistance to ADCs used in the clinic along with other potential ones that may contribute to resistance acquisition. We also discuss strategies to overcome resistance to ADCs.
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...the cumulative incidence of FPIES was (1) 0.35% for cow's milk protein, (2) 0.26% for fish, and (3) 0.09% for egg yolk. First and second doses were separated by 45 minutes and second and third ...doses by 2 hours. Case Sex Age of onset (mo) Trigger food Diagnostic criteria for patients presenting with possible FPIES Diagnostic criteria for the interpretation of OFCs in patients with a history of possible or confirmed FPIES Age of OFC (mo) Treatment Recovery Case 1 Male 4 Cow's milk (infant formula) With lower doses of cow's milk, intermittent vomiting with failure to thrive (chronic FPIES) Vomiting in the 1-4-h period after ingestion of the cow's milk protein without allergic skin or respiratory symptoms Extreme lethargy and marked pallor with the reaction 13 No No Case 2 Male 4 Cow's milk (infant formula) Vomiting in the 1-4-h period after ingestion of the cow's milk protein without allergic skin or respiratory symptoms More episodes of repetitive vomiting after eating the same suspect food Vomiting in the 1-4-h period after ingestion of the cow's milk protein without allergic skin or respiratory symptoms Extreme lethargy and marked pallor with the reaction Diarrhea 5-10 h after food ingestion 4 Intravenous fluid support Ondansetron No Case 3 Female 4 Cow's milk (infant formula) Vomiting in the 1-4-h period after ingestion of the cow's milk protein without allergic skin or respiratory symptoms More episodes of repetitive vomiting after eating the same suspect food Extreme lethargy and marked pallor with the reaction Need for emergency department visit with any suspected reaction OFC was not conducted because of repeated reactions to cow's milk protein. Patient meets diagnostic criteria for acute FPIES — — No Case 6 Male 13 Fish Vomiting in the 1-4-h period after ingestion of hake without allergic skin or respiratory symptoms One more episode of repetitive vomiting after eating the same suspect food Need for emergency department visit with the reaction Vomiting in the 1-4-h period after ingestion of the cow's milk protein without allergic skin or respiratory symptoms Extreme lethargy and marked pallor with the reaction 23 Intravenous fluid support Ondansetron No Case 7 Female 15 Fish Vomiting in the 1-4-hour period after ingestion of hake without allergic skin or respiratory symptoms One more episode of repetitive vomiting after eating the same suspect food Vomiting in the 1-4-h period after ingestion of the cow's milk protein without allergic skin or respiratory symptoms Extreme lethargy and marked pallor with the reaction Diarrhea 5-10 h after food ingestion 18 Intravenous fluid support Ondansetron No Case 8 Male 6 Cow's milk (infant formula) Vomiting in the 1-4-h period after ingestion of hake without allergic skin or respiratory symptoms Vomiting in the 1-4-h period after ingestion of the cow's milk protein without allergic skin or respiratory symptoms Extreme lethargy and marked pallor with the reaction 24 Intravenous fluid support Ondansetron No Table I Case summary∗
Trastuzumab-emtansine (T-DM1) is an antibody-drug conjugate (ADC) that was approved recently to treat HER2
breast cancers. Despite its impressive clinical efficacy in many patients, intrinsic and ...acquired resistance to T-DM1 has emerged as a challenge. To identify mechanisms of T-DM1 resistance, we isolated several resistant HER2
clones exhibiting stable drug refractoriness
and
Genomic comparisons showed substantial differences among three of the isolated clones, indicating several potential mechanisms of resistance to T-DM1. However, we observed no differences in HER2 levels and signaling among the resistant models and parental HER2
cells. Bioinformatics studies suggested that intracellular trafficking of T-DM1 could underlie resistance to T-DM1, and systematic analysis of the path followed by T-DM1 showed that the early steps in the internalization of the drug were unaltered. However, in some of the resistant clones, T-DM1 accumulated in lysosomes. In these clones, lysosomal pH was increased and the proteolytic activity of these organelles was deranged. These results were confirmed in T-DM1-resistant cells from patient-derived HER2
samples. We postulate that resistance to T-DM1 occurs through multiple mechanisms, one of which is impaired lysosomal proteolytic activity. Because other ADC may use the same internalization-degradation pathway to deliver active payloads, strategies aimed at restoring lysosomal functionality might overcome resistance to ADC-based therapies and improve their effectiveness.
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Adult neurogenesis is involved in cognitive performance but studies that manipulated this process to improve brain function are scarce. Here, we characterized a genetic mouse model in which neural ...stem cells (NSC) of the subventricular zone (SVZ) were temporarily expanded by conditional expression of the cell cycle regulators Cdk4/cyclinD1, thus increasing neurogenesis. We found that supernumerary neurons matured and integrated in the olfactory bulb similarly to physiologically generated newborn neurons displaying a correct expression of molecular markers, morphology and electrophysiological activity. Olfactory performance upon increased neurogenesis was unchanged when mice were tested on relatively easy tasks using distinct odor stimuli. In contrast, intriguingly, increasing neurogenesis improved the discrimination ability of mice when challenged with a difficult task using mixtures of highly similar odorants. Together, our study provides a mammalian model to control the expansion of somatic stem cells that can in principle be applied to any tissue for basic research and models of therapy. By applying this to NSC of the SVZ, we highlighted the importance of adult neurogenesis to specifically improve performance in a challenging olfactory task.
Synopsis
A transitory expansion of neural stem cells results in an increase in adult born neurons that functionally integrate in the mouse olfactory bulb. These neurons improve the performance of challenging olfactory tasks by increasing the discrimination of similar odorants.
A novel mouse model for the inducible and tissue‐specific expression of Cdk4/cyclinD1 (4D) allows the expansion of somatic stem cells.
Expansion of neural stem cells in the adult subventricular zone triggers the long‐term increase in adult neurogenesis.
Supernumerary neurons can physiologically migrate, mature and integrate in the olfactory bulb circuitry.
Mice with increased adult neurogenesis are better specifically at discriminating highly similar odorants.
Our mouse model might provide an important tool toward investigating the use of somatic stem cells for recovery of organ function in disease models.
Surplus olfactory neurons induced in adult mice are not only functionally and morphologically integrated, but can also contribute to enhanced sensory performance on a challenging olfactory task.
Designing urban water systems to respond to the accelerating and unpredictable changes of the Anthropocene will require changes not only to built infrastructure and operating rules, but also to the ...governance arrangements responsible for investing in them. Yet, inclusion of this political‐economic feedback in dynamic models of infrastructure systems and socio‐hydrology has lagged behind operational feedback concerns. We address this gap through a dynamical systems application of the Coupled Infrastructure Systems (CIS) Framework, which provides the conceptual building blocks for analyzing social‐ecological systems through various classes of infrastructure and the flows of material and information among them. In the model, political‐economic feedback involves three decisions—infrastructure investment, rate‐setting, and short‐term demand curtailment—and each decision is constrained by institutional friction, the aggregation of decision and transaction costs associated with taking action. We apply the model to three cities in the Phoenix Metropolitan Area to compare how institutional friction interacts with a city's water resource portfolio and financial position to determine its sensitivity, or the degree to which its performance (e.g., providing sufficient supply to meet demand) changes given reductions in Colorado River water availability. We find that the slowing effect of institutional friction on investment and rate‐setting decisions can increase the sensitivity of a city's supply, but it can also promote objectives that compete with over‐response (e.g., rate burden). The effect is dependent on the initial operating capacity of the CIS and flexibility within the institutions, highlighting the need to consider political‐economic and operational feedback together when evaluating infrastructure systems.
Plain Language Summary
Urban water systems must grapple with accelerating social and environmental change that requires them to not only consider future infrastructure needs, but also, the configuration of decisions responsible for infrastructure investment. Unfortunately, inclusion of political‐economic feedback has lagged behind operational feedback in models that examine water systems response to changing environments. We present a modeling approach to trace the flow of water, information, and investment in a general urban water system that must make three annual decisions: infrastructure investment, rate‐setting, and short‐term demand curtailment. Each decision is influenced by costs to taking action and the flexibility involved in setting action magnitudes. We apply the model to three cities in the Phoenix Metropolitan Area to compare how these institutional constraints interact with existing infrastructure and finances to affect their sensitivity, or the degree to which their performance (e.g., providing sufficient supply to meet demand) changes given reductions in Colorado River water. We find that when institutional barriers to action increase, cities are more sensitive to supply shocks, but such barriers can benefit other objectives like rate burden. The effect is dependent on the presence of redundant supplies, demand growth, and decision‐making flexibility, highlighting the need to consider both political‐economic and operational concerns when evaluating water systems.
Key Points
Having sufficient supply redundancy can outweigh the negative effect of slow institutions on a city's ability to address supply shocks
The supplies of cities with institutions that require more stress to act are more sensitive to shocks, but their rates are less sensitive
Adding flexibility to institutions can ease the burden of large investments on ratepayers and improve the reliability of slow institutions
The kinase suppressor of rat sarcoma (RAS) proteins (KSR1 and KSR2) have long been considered as scaffolding proteins required for optimal mitogen‐activated protein kinase (MAPK) pathway signalling. ...However, recent evidence suggests that they play a more complex role within this pathway. Here, we demonstrate that ectopic expression of KSR1 or KSR2 is sufficient to activate the MAPK pathway and to induce cell proliferation in the absence of RAS proteins. In contrast, the ectopic expression of KSR proteins is not sufficient to induce cell proliferation in the absence of either rapidly accelerated fibrosarcoma (RAF) or MAPK‐ERK kinase proteins, indicating that they act upstream of RAF. Indeed, KSR1 requires dimerization with at least one member of the RAF family to stimulate proliferation, an event that results in the translocation of the heterodimerized RAF protein to the cell membrane. Mutations in the conserved aspartic acid–phenylalanine–glycine motif of KSR1 that affect ATP binding impair the induction of cell proliferation. We also show that increased expression levels of KSR1 decrease the responsiveness to the KRASG12C inhibitor sotorasib in human cancer cell lines, thus suggesting that increased levels of expression of KSR may make tumour cells less dependent on KRAS oncogenic signalling.
Ectopic expression of kinase suppressor of rat sarcoma (RAS) 1 or 2 (KSR1 or KSR2) induces cell proliferation in the absence of RAS. RAS‐independent proliferation occurs via mitogen‐activated protein kinase (MAPK) pathway activation through the heterodimerization and activation of rapidly accelerated fibrosarcoma (RAF) proteins, an activity that requires their plasma membrane localization and ATP binding. Increased expression levels of KSR make tumor cells less dependent on KRAS signaling and thus possibly less responsive to KRAS inhibitors.
Refining Early Antitumoral Drug Development Ocaña, Alberto; García-Alonso, Sara; Amir, Eitan ...
Trends in pharmacological sciences (Regular ed.),
November 2018, 2018-11-00, 20181101, Letnik:
39, Številka:
11
Journal Article
Recenzirano
The failure rate of development of new drugs in oncology is high, with up to 95% of drugs tested in Phase I not reaching the market. Causes behind this high failure rate are discussed here, and ...solutions to increase the success in the development of antitumor drugs are suggested.
The scientific literature related to human resource management (HRM) and sustainability has increased since 2015, coinciding with the establishment of the 2030 Agenda for Sustainable Development. ...This article combines a bibliometric approach, using VOSviewer and SciMat software, with a systematic literature review to assess and identify the scientific production in this domain. During the period studied (1996–2023), the results reveal the role of HR in achieving corporate sustainability but also the responsibility of companies to apply sustainable principles to HRM practices. Based on the findings and the less developed issues related to the SDGs and HRM a model of research proposals is provided, focusing on mental health (SDG 3), gender equality (SDG 5), collaboration towards climate action and responsible production and consumption (SDGs 12 & 13), and more emphasis on SDG 1 regarding the social sustainability of organisations.
Introduction
The histological transformation (HT) of follicular lymphoma (FL) is a crucial biological event. The study aimed to evaluate the incidence, clinicial characteristics, prognosis and impact ...of HT time on survival of FL transforming to diffuse large B‐cell lymphoma in population‐based large‐scale cohorts.
Methods
A retrospective cohort study of FL with HT was performed in the Surveillance, Epidemiology, and End Results database. The Hematological Malignancy Research Network FL cohort and Aristotle study FL cohort were used to assess the external validity.
Results
Among 44,127 FL cases from the Surveillance, Epidemiology, and End Results database, 1311 cases were pathology‐proven recorded to transform to diffuse large B‐cell lymphoma. The cumulative rates of HT at 5, 10, and 15 years after FL diagnosis were estimated to be 1.19%, 2.93%, and 5.01%, respectively. Significantly worse overall survival and cancer‐specific survival were exhibited in patients with HT than those without HT. Early HT (transformation of FL within 48 months after FL diagnosis TOD48) was an independent predictor for adverse overall survival of HT patients, regardless of treatment modalities before transformation. The adverse prognostic effect of TOD48 was validated in the Hematological Malignancy Research Network cohort and Aristotle study cohort. Older age (>75 years) and B symptoms within FL at diagnosis were the independent risk factors of TOD48. Furthermore, a novel prognostic model combining TOD48 with Follicular Lymphoma International Prognostic Index (TOD48‐FLIPI) was constructed and validated for risk stratification.
Conclusion
TOD48 was a risk indicator of HT, and the novel prognostic model "TOD48‐FLIPI" for HT patients was proposed.
The population‐based retrospective cohort study showed that histological transformation of follicular lymphoma to diffuse large B‐cell lymphoma within 48 months after follicular lymphoma diagnosis (TOD48) was associated with poor survival. A novel prognostic model consisting of TOD48 and Follicular Lymphoma International Prognostic Index was proposed and validated for risk stratification.
Summary
Although follicular lymphoma (FL) patients relapsing within 24 months after first‐line treatment (POD24) have a poor prognosis, some cases show notable survival after first relapse (SF1R). We ...aimed to characterize the POD24 FL population and to identify the main prognostic factors at progression. We selected 162 POD24 patients (80F; median age at first relapse 59 years) from a cohort of 1067 grades 1‐3a FL‐treated patients. The remaining 905 patients treated with first‐line immunochemotherapy and diagnosed during the same period were used to compare outcomes in terms of survival. After a median follow‐up of 11.0 years, 96 patients died (10y‐SF1R of 40%). Age over 60 years (p < 0.001), high lactate dehydrogenase (LDH) (p < 0.001), haemoglobin (Hb) less than 120 g/L (p < 0.001), advanced stage (p < 0.001), high‐risk Follicular Lymphoma International Prognostic Index (FLIPI) (p < 0.001), histological transformation (HT) (p < 0.001) and reaching less than complete response (CR) after salvage therapy (p < 0.001), predicted poor SF1R at relapse. In multivariate analysis only high‐risk FLIPI and HT maintained prognostic significance for SF1R. POD24 patients not transformed and with low/intermediate FLIPI at relapse behaved better than the remaining cases. POD24 patients showed an excess mortality of 38% compared to the general population. Although outcome of POD24 FL patients is poor, a considerable group of them (low/intermediate FLIPI and not transformed at first relapse) behave better.
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