Natalia Díaz Valdivia and Jordi Alcaraz.
Photo Credit: Courtesy of Universitat de Barcelona
Scientific Frontline: Extended "At a Glance" Summary: Dynamic BH3 Profiling in Lung Cancer Therapies
The Core Concept: Dynamic BH3 profiling (DBP) is an advanced functional assay that predicts the efficacy of specific cancer treatments by testing them directly on living tumor cells.
Key Distinction/Mechanism: Unlike genomic sequencing that solely identifies genetic mutations, DBP functionally measures a tumor's apoptotic response (programmed cell death), acting similarly to an antibiogram to determine if targeted therapies will be lethal to the specific cancer cells.
Major Frameworks/Components:
- ALK Inhibitors: Targeted drugs aimed at the 5% of NSCLC patients with alterations in the ALK oncogene; these inhibitors can effectively cross the blood-brain barrier to treat central nervous system metastases.
- Apoptosis Regulation: The critical cellular balance between pro- and anti-apoptotic proteins that dictates whether a tumor cell survives or succumbs to a therapeutic agent.
- BH3 Mimetics: Specialized small molecules that inhibit anti-apoptotic proteins. They are utilized to prevent acute tumor adaptation and overcome cellular resistance to primary treatments.
Branch of Science: Molecular Oncology, Precision Medicine, Cellular Biology, and Pharmacogenomics.
Future Application: Integrating DBP into routine clinical workflows to complement mass sequencing, enabling highly personalized drug selection for complex NSCLC cases and guiding the clinical use of combination therapies to preemptively neutralize tumor resistance.
Why It Matters: NSCLC accounts for 85% of all lung cancer diagnoses. Accurately predicting an individual's therapeutic response ensures patients receive the most effective targeted therapy early in the disease progression, maximizing survival rates and preserving quality of life while avoiding ineffective treatments.
“The study reveals that the fibroblast-rich tumor microenvironment is not merely a spectator but a key player that shapes the tumor’s progression. Tumor-associated fibroblasts can influence the vascular network, the availability of oxygen and nutrients, and, potentially, metastatic dissemination and the immune response,” explains Jordi Alcaraz, a professor at the University of Barcelona’s (UB) Faculty of Medicine and Health Sciences and a researcher at the Institute for Bioengineering of Catalonia (IBEC), the Hospital Clínic de Barcelona, and the CIBER Area for Respiratory Diseases (CIBERES), who led the research.
This is an international collaborative study whose first author is UB researcher Natalia Díaz Valdivia, and which involved experts from the Catalan Institute of Oncology, the Bellvitge Biomedical Research Institute (IDIBELL), the Mayo Clinic (United States), the Francis Crick Institute (United Kingdom), the Garvan Institute of Medical Research, and the University of New South Wales (Australia).
Enhancing the Impact of Immunotherapy
One of the most promising therapies against lung cancer—the leading cause of cancer-related death worldwide—is immunotherapy, a therapeutic approach that boosts the immune system’s ability to attack cancer cells. Despite its potential, most patients do not respond to immunotherapy, and one of the strategies proposed to increase its efficacy is to combine it with anti-angiogenic drugs, which can help normalize tumor blood vessels and reduce the suppression of the body’s immune response.
“Until now, squamous cell carcinoma, the second most common type of lung cancer, has been excluded from this promising combined therapeutic strategy because it has historically shown resistance to anti-angiogenic therapies, unlike lung adenocarcinoma, which is the most common subtype,” explains Jordi Alcaraz.
To analyze these differences, the researchers studied various markers related to blood vessel formation and oxygen deprivation in the main types of lung cancer. This comprehensive analysis enabled the identification of how tumor fibroblasts influence the formation of new blood vessels, an effect that was validated in patient samples and animal models.
The results show that adenocarcinoma exhibits much more active and functional angiogenesis, with higher oxygen levels and less cell death, whereas squamous carcinoma shows poorer formation of blood vessels within the tumor and a more acidic, hypoxic environment. According to the researchers, this difference largely depends on fibroblasts, which provide essential logistical support for tumor development and drug resistance.
“We have observed that, in adenocarcinoma, these fibroblasts promote the formation of blood vessels through a synergy between vascular endothelial growth factor and TIMP-1, a novel proangiogenic factor,” says the researcher.
Researchers discover why the two main types of lung cancer respond differently to drugs that target blood vessels, a finding that opens the door to more effective therapies.
“By contrast,” he continues, “in squamous cell carcinoma, blood vessel formation is inefficient due to molecular changes in the associated fibroblasts resulting from higher tobacco exposure, which leads to tumors with lower oxygen levels—that is, more hypoxic.”
These results have several biomedical implications. First, they help explain why anti-angiogenic treatments have historically been effective in lung adenocarcinoma but not in squamous cell carcinoma.
On the other hand, the increased angiogenesis observed in adenocarcinoma provides, according to the researchers, a simple explanation for why these tumors tend to metastasize earlier than squamous cell carcinoma, since metastasis requires tumor cells to access the blood vessel network in order to spread.
Toward More Precise and Effective Therapies
These differences in the tumor microenvironment reinforce the idea that the different subtypes of lung cancer require different therapeutic strategies. “Especially now that combinations of immunotherapy and anti-angiogenic drugs play a central role in oncology,” adds Alcaraz.
In this regard, the researchers propose that, rather than applying uniform approaches, both angiogenesis and the tumor microenvironment should be incorporated as criteria for stratifying patients and selecting treatments.
This could include the use of biomarkers such as TIMP-1 to identify tumors that are more dependent on molecular pathways that promote blood vessel formation, as well as the development of rational combinations of immunotherapy and microenvironment-targeted therapies. “For example, our results suggest that adenocarcinoma might benefit more from treatments targeting specific pro-angiogenic pathways such as SMAD3 or TIMP-1, whereas in squamous cell carcinoma it may be more relevant to target tumor hypoxia or acidosis,” notes Alcaraz.
The researchers also highlight the need to develop new therapeutic approaches against TIMP-1 in adenocarcinoma, as there is currently no specific inhibitor available.
In this context, the major current and future challenge is to translate these promising discoveries into the clinical setting: “We need to identify robust biomarkers, such as TIMP-1, validate them prospectively, and demonstrate that modulating the tumor microenvironment can truly improve patients’ therapeutic response,” concludes the UB professor.
Funding: This study was partially funded by grants from the Spanish National Research Council, the European Union’s Horizon 2020 research and innovation programme, and the Spanish Association Against Cancer.
Published in journal: Cell Death & Disease
Authors: Natalia Díaz-Valdivia, Paula Duch, Rafael Ikemori, Amelia L. Parker, Marselina Arshakyan, Alejandro Llorente, Alejandro Bernardo, José Rodríguez-Rojas, Josep Lluis Carrasco, Danielle Park, Erik Sahai, Cristina Fillat, Manel Juan, Ernest Nadal, Noemí Reguart, Derek C. Radisky, Oriol Casanovas, and Jordi Alcaraz
Source/Credit: Universitat de Barcelona
Edited by: Scientific Frontline
Reference Number: ongy060326_01
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