A carregar...
Publicação
MCT1 a peon in metabolic adaptation and a crucial target in lung cancer
| Nome: | Descrição: | Tamanho: | Formato: | |
|---|---|---|---|---|
| 29.86 MB | Adobe PDF |
Autores
Orientador(es)
Resumo(s)
Abstract
Lung cancer remains a global health challenge, with late-stage diagnosis and
treatment resistance contributing to its devastating impact. In the past two decades,
lung cancer therapy has witnessed notable progress, transitioning from cytotoxic
treatments to more tolerable and highly effective targeted regimens, particularly tailored
to specific molecular subtypes. Despite these advancements, challenges persist in the
treatment of metastatic disease, and the emergence of resistance mechanisms,
particularly in the context of targeted therapies, requires ongoing research to bridge
existing gaps in understanding and improve long-term survival outcomes.
The field of cancer metabolism has evolved significantly since the recognition of
metabolic reprogramming as a hallmark of cancer, challenging the traditional Warburg
dogma. Cancer cells adapt their metabolism to sustain rapid proliferation and tumor
growth, undergoing complex alterations in glucose, glutamine, lipid and redox
metabolism. The intricate interplay between oncogenic signaling, transcriptional
networks, and the tumor microenvironment (TME) further shapes metabolic remodeling
in cancer. Notably, lactate, a byproduct of glycolysis, influences the acidic TME,
impacting tumor growth, invasion, and immune response. Reactive oxygen species
(ROS) generated during oxidative metabolism play a dual role in cancer, influencing
both tumor progression and cellular damage. The heterogeneity of metabolic
alterations in non-small cell lung cancer (NSCLC) underscores the importance of
understanding context-dependent factors for targeted therapeutic interventions in
cancer metabolism.
The signaling pathways dependent on receptor tyrosine kinases (RTK), particularly
the epidermal growth factor receptor (EGFR), contribute to metabolic remodeling in
NSCLC. Approximately 15-30% of NSCLC tumors exhibit EGFR mutations, leading to
constitutive activation of the EGFR tyrosine kinase domain. This activation induces
abnormal signaling cascades that promote pro-survival and anti-apoptotic signals
through downstream targets. Mutations in the EGFR gene were previously reported to
promote metabolic reprogramming in NSCLC. However, it is still unclear whether the
metabolic changes induced by EGFR-driven reprogramming in cells expose
vulnerabilities that could be targeted for therapeutic benefits.
This thesis delves into the metabolic landscape of NSCLC, EGFR-mutant NSCLC,
and explores innovative therapeutic approaches to exploit metabolic vulnerabilities. We
elucidate the metabolic heterogeneity within EGFR-mutant NSCLC, revealing distinct
alterations in glucose and lactate bioavailability across NSCLC cell lines with varying
EGFR profiles. The study further explores the regulatory effects of EGF on monocarboxylate transporters (MCTs), highlighting the role of MCT1 in lactate
metabolism. These findings underscore the importance of understanding NSCLC
metabolism for personalized treatment strategies.
The potential of Selenium-Chrysin (SeChry), a selenocompound derived from
natural chrysin, in modulating redox homeostasis and metabolic vulnerabilities in
NSCLC was also explored. SeChry treatment induced distinct metabolic shifts,
impacting selenocompound metabolism and disrupting key metabolites, leading to
disruptions in redox homeostasis. This study explores the feasibility of combining
SeChry with other agents and soft nanoparticles (polyurea dendrimers), unveiling
potential adjuvant nanotherapeutic strategies. SeChry@PUREG4-LA24, a SeChry
nanoformulation, where SeChry is encapsulated in a generation four lactic acid (LA)
targeted polyurea (PURE) dendrimer, is evaluated as a promising strategy for NSCLC
treatment. Results demonstrated varying sensitivities among NSCLC cell lines, with
SeChry@PUREG4-LA24 inducing cell death patterns suggestive of necrosis/necroptosis.
The efficacy of SeChry@PUREG4-LA24 was also evaluated in in vivo models, using the
chicken embryo chorioallantoic membrane (CAM) assay and murine models. In the
CAM assay, H292 and PC-9-derived tumors treated with SeChry@PUREG4-LA showed
reduced tumor size and blood vessel area, emphasizing the potential of
SeChry@PUREG4-LA24 in TME targeting. In murine models, animals treated with
SeChry@PUREG4-LA24, using an inhalation approach, presented a significant reduction
in tumor burden and cachexia.
Overall, this thesis provides relevant insights into the complex metabolic landscape
of NSCLC, laying the groundwork for precision cancer management. The results
emphasize the promising potential of addressing metabolic vulnerabilities for the
development of innovative and personalized therapeutic strategies in NSCLC.
Descrição
Palavras-chave
Non-small cell lung cancer (NSCL) cancer metabolism metabolic heterogeneity metabolic remodeling epidermal growth factor receptor (EGFR) metabolism-based therapy selenium-containing chrysin (SeChry) SeChry encapsulated in lactate targeted generation four polyurea dendrimer (SeChry@PUREG4-LA24)