Research Laurie Freire Boullosa

Abstract

Non-small cell lung cancer (NSCLC) and pancreatic cancer (PDAC) are two of the most common and lethal malignancies worldwide. Survival outcomes for the majority of these patients remain very poor due to an advanced stage at diagnosis and their rapid progressive nature. The first-line treatment of advanced NSCLC in most patients still consists of conventional chemotherapy to achieve tumor response or stable disease. Current treatment options for PDAC are limited since only 10-20% of the patients is eligible for curative surgical resection. The remaining patient population is treated with gemcitabine/nab-paclitaxel or FOLFIRINOX which have only modest improvements in survival due to chemoresistance in most patients. Therefore, there is a high unmet need for novel and more effective treatment approaches for both cancer types. This dire need for new therapeutic options encouraged me to provide the fastest way towards clinical application. Therefore, we used the orally available, lipophilic, organogold compound Auranofin (AF), which is included in the list of the ReDo (Repurposing Drugs in Oncology) project established by the Belgian non-profit Anticancer fund. I was the first to show the therapeutic anticancer potential of AF in mutant p53 NSCLC and PDAC cancer cell lines in which it triggered distinct molecular cell death mechanisms (apoptosis, ferroptosis and immunogenic cell death) by inhibiting the thioredoxin and glutathione redox systems and inducing oxidative stress (Freire Boullosa et al., 2021). Furthermore, I showed the relevance of targeting thioredoxin reductase in NSCLC patients, since it is overexpressed in NSCLC cells compared to the surrounding tissue. Despite these promising results as a single agent, I am convinced that the true power of AF lies within rationally designed drug combination strategies. This is supported by my recent work on the highly synergistic combination of AF and the PARP-1 inhibitor Olaparib which is effective in in vitro and in vivo NSCLC and PDAC models (ongoing). In addition, an increasing number of publications highlights the potential of AF in combination with chemotherapeutic agents, mTOR inhibitors, ROS inducers, etc. which resulted in several Phase I and II clinical trials. Therefore, the goal of this study is to perform a high-throughput drug combination screening with AF and a literature-based / clinically available drug panel based on standard of care regimens and inhibitors of KRAS effector pathways, in a set of patient-derived NSCLC and PDAC 3D organoids using our in-house developed drug screening platform Orbits. This allows us to study for the first time which AF drug combination strategies are the most promising and which baseline patient characteristics are related to therapy response using the most clinically relevant in vitro model available to date based on the genomic and transcriptomic characterization of these organoid lines. Overall, drug repurposing of the off-patent drug AF will contribute to a positive impact on patient outcome and quality of life, to a faster clinical implementation and to a lower healthcare cost.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: Deben Christophe
• Fellow: Freire Boullosa Laurie

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Despite several recent breakthroughs, lung cancer remains the leading cause of cancer-related death worldwide. Non-small cell lung cancer is characterized by a 5-year survival rate of less than 20%, which is often the result of resistance mechanisms against current therapies. In our search for new anticancer therapies, we discovered that Auranofin, an old drug currently used for rheumatoid arthritis, is highly effective against mutant p53 expressing cancer cells. P53 is the most frequently mutated gene in lung cancer and is often associated with an unfavorable therapeutic outcome. Auranofin is a selective inhibitor of the antioxidant thioredoxin reductase. Previous studies have shown that Auranofin dependent inhibition of this antioxidant blocks several pro-tumorigenic pathways. Recent findings have shown that these pathways are also involved in attracting immunosuppressive cells to the tumor microenvironment and in hiding cancer cells from immune cells. To date, little is known about the underlying mechanisms by which AF induces cancer cell death and if Auranofin can modulate the immune suppressive tumor microenvironment. In this strategic basic research project, we recently discovered that Auranofin induces different types of immunogenic cell death pathways, including the type of cellular 'rust' ferroptosis, which can stimulate the patient's immune cells to efficiently eliminate lung cancer cells. In addition, we will study the in vivo effect of Auranofin on different types of immune cells inside the tumor and peripheral blood to determine if Auranofin is a potential candidate for combination strategies with immunotherapy.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: Deben Christophe
• Fellow: Freire Boullosa Laurie

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Cancer treatment is advancing to personalized precision medicine following the continuous development of new targeted therapies and immunotherapies. Despite several recent breakthroughs, lung cancer remains the leading cause of cancer-related death worldwide. Non-small cell lung cancer is characterized by a 5-year survival rate of less than 20%, which is often the result of resistance mechanisms against current therapies. At the Center for Oncological Research we focused on targeting the tumor suppressor p53 protein to overcome resistance to conventionally used DNA-damaging agents. We showed that therapeutic reactivation of either wild type or mutant p53 greatly increased the cytotoxic response to cisplatin in a synergistic manner. Now we want to further improve these results by involving the immune system in the antitumor effect. Therefore, this study will explore the potential of p53 targeting therapies, as monotherapy or in combination with the DNA-damaging agent cisplatin, to eliminate tumor cells by recruitment and activation of natural killer (NK) cells. The outcome of this study could result in an innovate therapeutic strategy which combines a DNA-damaging agent with state-of-the-art targeted- and immunotherapy. As such, tumor cells can be targeted more directly and eliminated using the patient's own defense systems.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: Deben Christophe
• Fellow: Freire Boullosa Laurie

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Cancer treatment is advancing to personalized precision medicine following the continuous development of new targeted therapies and immunotherapies. Despite several recent breakthroughs, lung cancer remains the leading cause of cancer-related death worldwide. Non-small cell lung cancer is characterized by a 5-year survival rate of less than 20%, which is often the result of resistance mechanisms against current therapies. At the Center for Oncological Research we focused on targeting the tumor suppressor p53 protein to overcome resistance to conventionally used DNA-damaging agents. We showed that therapeutic reactivation of either wild type or mutant p53 greatly increased the cytotoxic response to cisplatin in a synergistic manner. Now we want to further improve these results by involving the immune system in the antitumor effect. Therefore, this study will explore the potential of p53 targeting therapies, as monotherapy or in combination with the DNA-damaging agent cisplatin, to eliminate tumor cells by recruitment and activation of natural killer (NK) cells via the receptor NKG2D. For this, we will study (I) the p53 dependent induction of NKG2D ligand expression and NK cell targeting chemo- and cytokine secretion in a panel of NSCLC cell lines; (II) NK cell-mediated NSCLC tumor cell killing in co-culture experiments; and (III) the potential additional antitumor effect of interleukin 15 as potent NK cell activator. The outcome of this study could result in an innovate therapeutic strategy which combines a DNA-damaging agent with state-of-the-art targeted- and immunotherapy. As such, tumor cells can be targeted more directly and eliminated using the patient's own defense systems.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: Deben Christophe
• Fellow: Freire Boullosa Laurie

Research team(s)

Project type(s)

• Research Project