1.Understanding the dual role of autophagy in cancer and therapeutic implications

Autophagy is a cellular process that involves the degradation and recycling of cellular components, helping to maintain cell health by clearing damaged proteins and organelles. In the context of cancer, autophagy plays as a tumor suppressor by preventing the buildup of potentially harmful cellular debris, thereby safeguarding against malignant transformation. However, in established tumors, autophagy can switch roles and support cancer survival. It enables cancer cells to cope with metabolic and therapeutic stresses, thus promoting tumor growth and resistance to treatments. This complex role of autophagy in cancer highlights its importance as a relevant target in cancer therapy strategies.

In this frame of research, my interests are:

• To dissect the molecular mechanisms that link the autophagy process with the acquisition of chemoresistance.

• To investigate the complex interplay between autophagy and metabolism and its impact on tumor cell invasion.

• To develop therapeutic strategies based on modulating autophagy to reverse chemoresistance.

• To use drug repurposing approaches to identify potential candidates for further in vivo evaluation.

Five publications related: 

-Evaluation of Mitochondrial Phagy (Mitophagy) in Human Non-small Adenocarcinoma Tumor Cells. Methods Mol Biol. 2024 Apr 13. doi:10.1007/7651_2024_532. Procotol. 

-Immune checkpoints between epithelial-mesenchymal transition and autophagy: A conflicting triangle. Cancer Lett. 2024 Mar 31;585:216661. doi: 10.1016/j.canlet.2024.216661. Review IF: 9.7  (First name)

-The obesity-autophagy-cancer axis: Mechanistic insights and therapeutic perspectives. Semin Cancer Biol. 2024 Feb;99:24-44. doi:10.1016/j.semcancer.2024.01.003. Review.  IF: 14.5 (Co-first name)

-Metastatic outgrowth via the two-way interplay of autophagy and metabolism. Biochim Biophys Acta Mol Basis Dis. 2024 Mar;1870(3):166824. doi: 10.1016/j.bbadis.2023.166824. Review. IF: 6.2 (Co-first name)

-Gasdermin B over-expression modulates HER2-targeted therapy resistance by inducing protective autophagy through Rab7 activation. J Exp Clin Cancer Res. 2022 Sep 26;41(1):285. doi: 10.1186/s13046-022-02497-w. Research Article. IF: 11.3

2.Role of mutant p53 proteins in metabolic reprogramming and chemoresistance

Over four decades of research have confirmed the p53 tumor suppressor as a crucial defense against tumor development, capable of activating various pathways to maintain cellular and genomic stability. Missense mutations in the TP53 gene, prevalent in many cancers, not only diminish these tumor-suppressing activities but also endow mutant p53 proteins with aggressive traits that enhance cancer progression, invasion, and drug resistance. I am deeply interested in study how mutant p53 proteins adapt to and manipulate cellular stress and how affects metabolic reprogramming, potentially offering new insights into vulnerabilities within TP53-mutated cancers.

My specific aims in this line of research are: 

• To dissect if mutant p53 proteins regulate lipid metabolism and its interplay with autophagy process and tumor progression.

• To evaluate if mutant p53 alters the sensitivity to chemotherapy drugs in cellular and animal models of glioma, lung, and pancreatic cancer.

• To evaluate the effect of specific p53 mutations on cannabinoid-based therapies and dissect the molecular mechanisms underlying.

Five publications related: 

-Oncogenic pathways activated by pro-inflammatory cytokines promote mutant p53 stability: clue for novel anticancer therapies. Cell Mol Life Sci. 2021 Mar;78(5):1853-1860. doi: 10.1007/s00018-020-03677-7. Perspectives. IF: 8.0

-Mutant p53 induces SIRT3/MnSOD axis to moderate ROS production in melanoma cells. Arch Biochem Biophys. 2020 Jan 15;679:108219. doi: 10.1016/j.abb.2019.108219. Research Article. IF: 3.9

-Mutant p53 blocks SESN1/AMPK/PGC-1alpha/UCP2 axis increasing mitochondrial O(2-). production in cancer cells. Br J Cancer. 2018 Oct;119(8):994-1008. doi: 10.1038/s41416-018-0288-2. Research Article IF: 5.416 (First name)

-Molecular interplay between mutant p53 proteins and autophagy in cancer cells. Biochim Biophys Acta Rev Cancer. 2017 Jan;1867(1):19-28. doi: 10.1016/j.bbcan.2016.11.003. Review IF: 9.452 (First name)

- Mutant p53 proteins counteract autophagic mechanism sensitizing cancer cells to mTOR inhibition. Molecular Oncol. 2016 Aug;10(7):1008-29. doi: 10.1016/j.molonc.2016.04.001. Research Article IF: 5.34 (First name)

3.Development of innovative cancer therapies based on stimuli-responsive nanomaterials for drug delivery

Schematic diagram of stimuli-responsive gold nanocarriers for gene delivery. García-Garrido, E.; Cordani, M.; Somoza, Á. Modified Gold Nanoparticles to Overcome the Chemoresistance to Gemcitabine in Mutant p53 Cancer Cells. Pharmaceutics 2021, 13, 2067. https://doi.org/10.3390/pharmaceutics13122067 CC BY 4.0 DEED

Nanomedicine has significantly advanced cancer treatment through developments in materials science, chemistry, and their integration with biological systems. Nanoparticles (NPs) are small particles typically ranging from 1 to 100 nanometers, offering substantial benefits for biomedical applications. They feature customizable size, surface properties, and diverse encapsulation capabilities, enabling precise targeting of tumor sites, enhanced drug bioavailability, and reduced systemic toxicity. Recent research has emphasized the development of stimuli-responsive nanomaterials that utilize environmental triggers within the tumor microenvironment to optimize drug release, thus enhancing the therapeutic impact against cancer. Alongside chemically synthesized NPs, extracellular vesicles (EVs) derived from biological sources are particularly notable for their biocompatibility and inherent cellular targeting properties, which significantly enhance drug delivery precision.

To address this therapeutic strategy, my aims are to develop the following points:

• To evaluate the potential of extracellular vesicles for targeted drug delivery in tumor models.

• To assess the efficacy of cannabinoids encapsulated in biodegradable polymeric nanoparticles for cancer therapy.

• To develop and evaluate stimuli responsive gold nanoparticles, niosomes, and nanopolymers, specifically designed for the delivery of nucleic acids targeting the gain-of-function mutations in mutant p53 in cancer cells. 

Five publications related: 

-Modified Gold Nanoparticles to Overcome the Chemoresistance to Gemcitabine in Mutant p53 Cancer Cells. Pharmaceutics. 2021 Dec 3;13(12):2067. doi: 10.3390/pharmaceutics13122067. Research Article. IF: 6.321 (Co-corresponding author)

-A comparison study between doxorubicin and curcumin co-administration and co-loading in a smart niosomal formulation for MCF-7 breast cancer therapy. Eur J Pharm Sci. Dec 1;191:106600. doi: 10.1016/j.ejps.2023.106600. Research Article. IF: 5 (Co-corresponding author)

-Smart Modification on Magnetic Nanoparticles Dramatically Enhances Their Therapeutic Properties. Cancers (Basel). 2021 Aug 14;13(16):4095. doi: 10.3390/cancers13164095. Research Article. IF: 6.575

-Albumin-based nanostructures for uveal melanoma treatment. Nanomedicine. 2021 Jul;35:102391. doi: 10.1016/j.nano.2021.102391. Research Article IF: 6.575

-Water Soluble Iron-Based Coordination Trimers as Synergistic Adjuvants for Pancreatic Cancer. Antioxidants (Basel) 2021 Jan 7;10(1):66. doi: 10.3390/antiox10010066. Research Article IF: 7.675 (First author)