ProfessorGuido Franzoso, MD PhD

Professor Franzoso’s research interest is in the regulation, function, and therapeutic exploitation of the NF-κB transcription factor pathway. His research integrates molecular medicine with functional genomics to clarify the biology of NF-κB in human disease and develop actionable therapeutic routes and cognate targeted interventions to harness the extensive translational potential of the NF-κB pathway, with a focus on oncology.

Professor Franzoso’s research has made important contributions to translational medicine and NF-κB biology. In the 1990s, he contributed to the fundamental discovery that NF-κB activation depends on site-specific phosphorylation and proteolysis of the inhibitor, IκBα (PNAS 1993, Science 1995, JBC 1996, MCB 1997). He further identified the Bcl-3 oncoprotein as a key regulator of select NF-κB dimers (Nature 1992, Cell 1993, EMBO J 1993). He went on to generate many of the earliest knockout models in the NF-κB field (Immunity 1997, Genes Dev 1997, J Exp Med 1998), leading to an entirely new understanding of how NF-κB governs immunity, lymphoid development and bone morphogenesis.

More recently, his research focus has been on unravelling the mechanisms that underpin NF-κB-dependent cancer aetiopathogenesis and translating them into effective therapies. A large body of genetic, biochemical and clinical evidence unequivocally implicates aberrant NF-κB signalling as a central aetiopathogenic driver of malignancy and other major threats to global human health, including vascular, metabolic and chronic inflammatory diseases. Yet, despite an aggressive effort by the pharmaceutical industry dating back three decades, no specific NF-κB inhibitor has been clinically approved, due to the preclusive toxicities of systemic NF-κB blockade.

The conundrum in therapeutically targeting NF-κB has been achieving cancer-selective specificity, given the ubiquitous and pleiotropic functions of the NF-κB pathway. Over the last decade, Professor Franzoso’s discoveries in the areas of gene regulation and molecular oncology have enabled the deployment of novel therapeutic strategies that overcome this problem by targeting the non-redundant, cancer-specific downstream effectors of NF-κB-driven malignant aetiopathogenesis, rather than NF-κB itself. His pioneering research in this area demonstrated that the cancer-selective inhibition of the NF-κB pathway is possible and can yield a novel class of anti-cancer therapeutics that couple efficacy and tolerability to create unique drug profiles of clinical utility for development in oncology.

Professor Franzoso’s current research focuses on three major areas of oncology:

1. Target discovery to human trials

Professor Franzoso’s “bench-to-bedside” research in this space is exemplified by his discovery of the NF-κB-dependent cell survival module, GADD45β/MKK7 (Nature 2001, Blood 2003, Nat Cell Biol 2004, JBC 2007, J Clin Invest 2008), and its subsequent translation into an actionable therapeutic target in multiple myeloma (MM) and diffuse large B-cell lymphoma (DLBCL), two distinct B-cell malignancies and areas of substantial unmet medical need. These discoveries spurred the launch of a highly successful drug-discovery programme, leading to the development of the first-in-class GADD45β/MKK7 inhibitor, DTP3, which selectively kills MM and DLBCL cells in vitro and in vivo and is not toxic to normal cells (Cancer Cell 2014, Toxicol Rep 2019, Br J Haematol 2019). DTP3 recently received regulatory approval and is currently being evaluated in a nationwide multi-centre phase I/II trial in patients with relapsed or refractory MM and DLBCL (EudraCT: 2021-004028-13). In order to translate this research into healthcare benefit, the MRC has awarded the DTP3 programme over £10M in grant funding, with continual support for more than 14 years.

Professor Franzoso went on to demonstrate that this cancer-selective NF-κB-targeting paradigm is broadly applicable across multiple areas of oncology, beyond MM and DLBCL. By devising bespoke unbiased genetic screens, he was able to deconstruct the NF-κB-dependent transcriptomes of malignant diseases with functional precision, leading to the discovery of novel cancer core vulnerabilities that govern tumour cell survival (EMBO J 2003, Cell 2004, MCB 2007), energy and redox metabolism (Nat Cell Biol 2011, J Clin Invest 2022), and tumour-based innate immunosuppression (Cancer Res 2018). Decoding these disease mechanisms was the key to developing actionable therapeutic routes in novel areas of unmet need within oncology, including colorectal carcinoma (CRC), hepatocellular carcinoma (HCC), and high-grade serous ovarian carcinoma (HGSOC). Building on this knowledge, he subsequently established cognate medicinal chemistry programmes to develop further targeted interventions that selectively block oncogenic NF-κB signalling in ways which were not possible before, whilst circumventing the inherent toxicities of conventional NF-κB-targeting drugs.

2. Cancer metabolism

One area of major translational interest stems from Professor Franzoso’s recent research in CRC which identified the triacylglycerol (TAG) and cholesteryl ester (CE) lipase, carboxylesterase 1 (CES1), as a central metabolic driver of aggressive disease and actionable therapeutic target downstream of NF-κB and other oncogenic pathways in distinct molecular tumour subtypes (J Clin Invest 2022; unpublished data). Each year, about one million people die from CRC globally, with mortality projected to double by 2040, thus making CRC a global public health problem. Yet, there are no effective therapies to treat the 95% of patients with advanced CRC, who present with microsatellite-stable (MSS)/proficient mismatch repair (pMMR) disease and are consequently refractory to immune-checkpoint immunotherapy. As such, there is a high demand for mechanistically novel therapies to improve the clinical management of CRC patients.

Building on his recent discoveries and aiming to address this major unmet medical need in CRC, Professor Franzoso coordinates a multi-disciplinary drug-discovery network that integrates skills in medicinal chemistry, computational science/AI, bioinformatics, metabonomics and molecular and clinical oncology to generate clinically useful CES1 inhibitors for development in advanced CRC. His laboratory demonstrated that this precision medicine approach, targeting tumour-based lipid catabolism via CES1, selectively ablates the metabolic plasticity that enables cancer cells to survive in the nutrient-insufficient tumour-microenvironment (TME) and adapt to metabolically diverse ectopic sites, thereby fuelling aggressive tumour clinical behaviour and metastasis.

Using small-molecule proto-therapeutics, he attained proof-of-mechanism for this novel CES1-targeting approach in clinically relevant animal models of MSS/pMMR CRC, demonstrating potent and on-target-selective anti-cancer activity in vivo, with no adverse effects and mechanistically consistent metabolic and pharmacodynamic (PD) signals. In parallel, his laboratory utilises human CRC datasets profiled by multi-omics to develop predictive biomarkers for patient stratification, with initial validation in patient-derived 3D organoid (PDO) co-cultures, tumour-on-chip model systems and syngeneic and patient-derived xenograft (PDX) models. His team also exploits the adjunct modalities of action of CES1 inhibitors in non-malignant cell populations of the TME to develop rational drug combinations with standard-of-care immuno-modulatory and anti-angiogenic agents. With this collaborative, multi-dimensional research approach, he seeks to create a robust data package of precision therapeutics and companion diagnostic assets to maximise the clinical utility of CES1 inhibitors in patients with advanced MSS/pMMR CRC and other hard-to-treat cancers.

3. Immuno-oncology

A further research area of intense investigation for drug development stems from Professor Franzoso’s recent discovery of a novel, NF-κB-dependent innate immune-checkpoint that restricts tumour-based inflammation and CD8+ T-cell trafficking into tumours (Cancer Res 2018; unpublished data). Using animal models of multiple cancer types that are refractory to immune-checkpoint immunotherapy, he demonstrated that myeloid-specific gene loss markedly increases pro-inflammatory macrophage activation, intra-tumoural CD8+ T-cell infiltration, and adaptive anti-tumour immune responses, ablating tumour growth. Notably, conditional gene deletion in the myeloid lineage also prompted the formation of intra-tumoural tertiary lymphoid structures (TLSs), which characterise the “hottest” type of tumours and portend strong clinical responses to immune-checkpoint immunotherapy across human cancer types. Collectively, these results identify an essential mechanism for the immunosuppressive activity of the TME that excludes CD8+ T-cells from tumours and provide an actionable therapeutic route in the myelomonocytic lineage for breaking TME-mediated immunosuppression and primary resistance to immune-checkpoint immunotherapy.

The development of effective immunotherapies, such as immune-checkpoint inhibitors, has revolutionised the treatment of cancer patients. However, major challenges remain, as the large majority of patients fail to respond to these therapies, due to the absence of a pre-existing intra-tumoural CD8+ T-cell infiltrate. Thus, the main barrier to effective immune-checkpoint immunotherapy is the presence of immunosuppressive mechanisms in the TME that actively exclude CD8+ T cells from tumours.

Professor Franzoso’s research seeks to overcome this barrier by targeting the newly discovered innate immune-checkpoint to generate small-molecule immuno-therapeutics capable of transforming tumours that lack a CD8+ T-cell infiltrate (“cold” tumours) into CD8+ T-cell-inflamed ones (“hot” tumours). By deploying this novel TME-targeting strategy, his laboratory aims to develop combination immunotherapies that are effective in patients with immunologically “cold” tumours and consequently extend the clinical utility of existing immune-checkpoint inhibitors to the broader cancer patient population of non-responders. To deliver of this medicinal chemistry programme, his laboratory is characterising the pro-inflammatory signalosome controlled by the newly identified innate immune-checkpoint. In parallel, his laboratory investigates the synergism of myeloid-specific gene loss (a mimicry of the novel class of immuno-therapeutics) with existing immune-checkpoint inhibitors to identify effective drug combinations for treating patients with “cold” tumours. Further, they utilise cancer patient datasets and primary human tumours extensively profiled by multi-omics and other high-throughput methods for predictive biomarker discovery. The objective of this companion diagnostic research is to relate the tissue-specific expression of the novel innate immune-checkpoint with clinical outcomes, tumour immuno-score, genetic and molecular profile of the cancer cells, and cellular composition, activation state and spatial distribution of non-malignant cell populations of the TME.

Selected publications:

1. De Smaele et al. (2001). Nature, 414: 308-313.
2. Zazzeroni et al. (2003). Blood, 102: 3270-3279.
3. Papa et al. (2004). Nat. Cell Biol., 6: 146-153.
4. Pham et al. (2004). Cell, 119: 529-542.
5. Papa et al. (2007). J. Biol. Chem., 282: 19029-19041.
6. Papa et al. (2008). J. Clin. Invest., 118: 1911-1923.
7. Mauro et al. (2011). Nat. Cell Biol., 13: 1272-1279.
8. Tornatore et al. (2014). Cancer Cell, 26: 495-508.
9. Verzella et al. (2018). Cancer Res., 78: 1275-1292.
10. Tornatore et al. (2019). Toxicol. Rep., 6: 369-379.
11. Tornatore et al. (2019). Br. J. Haematol., 185: 588-592.
12. Capece et al. (2022). J. Clin. Invest., 131: e137845.