Periodic Reporting for period 1 - ACT-PC (Actionable metabolite supplements to improve treatment response in pancreatic cancer)
Reporting period: 2024-05-01 to 2025-10-31
Metastatic pancreatic ductal adenocarcinoma (mPDAC) is still one of the deadliest cancers, with an extremely poor prognosis—especially for patients who do not respond to standard chemotherapy regimens such as FOLFIRINOX. A major clinical bottleneck is that more than half of patients show little or no benefit from treatment, and many succumb to the cancer within months. This creates an urgent unmet need to develop actionable strategies to overcome resistance and extend survival.
It is increasingly apparent that the gut microbiome and the immune system can influence tumour progression and the response to cancer treatment. Growing evidence suggests that microbiota-derived metabolites—small molecules produced by gut bacteria—can play a role in cancer therapy by shaping both drug sensitivity and anti-tumour immunity. In particular, we have contributed to show that metabolites such as 3-indole-acetic acid (3-IAA) and short-chain fatty acids (SCFAs) can modulate chemotherapy efficacy and immune function in general (Tintelnot J. et al., Nature 2023; Siracusa F. et al., Nature Immunology 2023).
However, translating these insights into clinically useful interventions is challenging because the underlying biology is complex, metabolite effects can depend strongly on context and interactions with other molecules, and diet adds further variability by shaping microbiome composition, metabolite production, and immune tone.
ACT-PC was conceived to close this translation gap by initiating preclinical validations of microbiota-derived metabolites as practical treatment enhancers in PDAC.
It is increasingly apparent that the gut microbiome and the immune system can influence tumour progression and the response to cancer treatment. Growing evidence suggests that microbiota-derived metabolites—small molecules produced by gut bacteria—can play a role in cancer therapy by shaping both drug sensitivity and anti-tumour immunity. In particular, we have contributed to show that metabolites such as 3-indole-acetic acid (3-IAA) and short-chain fatty acids (SCFAs) can modulate chemotherapy efficacy and immune function in general (Tintelnot J. et al., Nature 2023; Siracusa F. et al., Nature Immunology 2023).
However, translating these insights into clinically useful interventions is challenging because the underlying biology is complex, metabolite effects can depend strongly on context and interactions with other molecules, and diet adds further variability by shaping microbiome composition, metabolite production, and immune tone.
ACT-PC was conceived to close this translation gap by initiating preclinical validations of microbiota-derived metabolites as practical treatment enhancers in PDAC.
Activity 1- Measurement of metabolites and correlation with treatment response
We expanded the clinical evidence base by measuring serum 3-IAA in two independent cohorts of metastatic pancreatic cancer patients treated with chemotherapy. Across both new cohorts, higher serum 3-IAA appeared to correlate positively with overall survival, reinforcing earlier findings that 3-IAA is associated with clinically meaningful outcomes. Based on this, we initiated the process to screen an additional major cohort, aiming to explore the possibility of using 3-IAA as a biomarker for treatment response. Finally, using another cohort of pancreatic cancer patients, we also measured the concentration of SCFA and preliminary results did not show correlation with survival. The use of a more sensitive method to measure SCFA would be ideal; we are working on this.
Activity 2: Assessing the potential efficacy of immunotherapy combinations in mouse models
We conducted mouse-model testing to evaluate functional interactions between 3-IAA, SCFAs (notably butyrate), chemotherapy, and immune checkpoint inhibition. While 3-IAA supplementation enhanced chemotherapy efficacy, an unexpected and critical in vivo finding was that butyrate co-treatment seems to reverse this benefit in the specific mouse model tested. This highlights the non-linear and context-dependent nature of metabolite–metabolite interactions and underscores that not all “therapy-immune-boosting” metabolites synergise when combined; further studies are needed to confirm and mechanistically explain this result. In parallel, the planned GMP/chemical synthesis route for 3-IAA proved unfeasible within the budget, as the external partner required a substantial additional investment and our internal pharmacy assessment indicated a formal toxicology assessment would be required prior to clinical supply, creating major cost and procedural barriers. As a scientifically grounded alternative, the project pivoted to exploring evolutionary biology/engineering approaches to generate microbiota strains capable of producing high concentrations of 3-IAA, potentially enabling a translational route framed as microbiota-based biological modulation rather than a classic pharmacological intervention, with important implications for feasibility and regulatory complexity.
Activity 3 — IP strategy (scientific/technical implications)
In collaboration with the UKE institutional technology transfer office, we assessed the freedom-to-operate and patentability landscape for microbiota-derived metabolites, focussing on 3-IAA and potential combinations. We concluded that freedom-to-operate was not a major barrier; however, patenting 3-IAA alone as a supplementation therapy would likely require developing and synthesising a slightly modified derivative with stronger novelty, which at present would entail substantial investment.
The initial recommendation to prioritise combinations (e.g. with SCFAs) was directly tested in preclinical studies, but the observed antagonistic effect of butyrate reduced the immediate patent attractiveness of that specific combination, and therefore no formal patent filing was pursued within ACT-PC. Nonetheless, this work advanced translational readiness by clarifying that future IP opportunities are more likely to lie in biomarker-based stratification claims and/or microbiota-engineering approaches to increase endogenous 3-IAA production.
Activity 4 — Market positioning (technical relevance to commercial landscape)
We reviewed the current treatment and business landscape to understand where a 3-IAA–based approach (and possibly other microbial metabolites) could fit in pancreatic cancer care and in the wider field of cancer therapy. This review suggested that the strongest case for further development is the combination of 3-IAA with other metabolites, in a combination never done before and with the use of 3-IAA concentration levels in the blood as a biomarker to identify who is most likely to respond.
Activity 5 — Business positioning (routes grounded in scientific outcomes)
We pulled together our technical and feasibility findings into clear development and exploitation options using a Business Model Canvas approach. This showed that developing a modified 3-IAA compound and producing it under GMP conditions is currently too expensive for an early-stage academic program. We therefore defined three practical and complementary alternatives: (1) develop microbiota-based approaches (engineering/evolution) to boost the body’s own 3-IAA production, (2) pursue partnerships or licensing with biotech/pharma companies that have the required development infrastructure, and (3) develop a diagnostic/stratification route that uses blood 3-IAA levels as a biomarker to help identify patients who are more likely to respond to chemotherapy.
We expanded the clinical evidence base by measuring serum 3-IAA in two independent cohorts of metastatic pancreatic cancer patients treated with chemotherapy. Across both new cohorts, higher serum 3-IAA appeared to correlate positively with overall survival, reinforcing earlier findings that 3-IAA is associated with clinically meaningful outcomes. Based on this, we initiated the process to screen an additional major cohort, aiming to explore the possibility of using 3-IAA as a biomarker for treatment response. Finally, using another cohort of pancreatic cancer patients, we also measured the concentration of SCFA and preliminary results did not show correlation with survival. The use of a more sensitive method to measure SCFA would be ideal; we are working on this.
Activity 2: Assessing the potential efficacy of immunotherapy combinations in mouse models
We conducted mouse-model testing to evaluate functional interactions between 3-IAA, SCFAs (notably butyrate), chemotherapy, and immune checkpoint inhibition. While 3-IAA supplementation enhanced chemotherapy efficacy, an unexpected and critical in vivo finding was that butyrate co-treatment seems to reverse this benefit in the specific mouse model tested. This highlights the non-linear and context-dependent nature of metabolite–metabolite interactions and underscores that not all “therapy-immune-boosting” metabolites synergise when combined; further studies are needed to confirm and mechanistically explain this result. In parallel, the planned GMP/chemical synthesis route for 3-IAA proved unfeasible within the budget, as the external partner required a substantial additional investment and our internal pharmacy assessment indicated a formal toxicology assessment would be required prior to clinical supply, creating major cost and procedural barriers. As a scientifically grounded alternative, the project pivoted to exploring evolutionary biology/engineering approaches to generate microbiota strains capable of producing high concentrations of 3-IAA, potentially enabling a translational route framed as microbiota-based biological modulation rather than a classic pharmacological intervention, with important implications for feasibility and regulatory complexity.
Activity 3 — IP strategy (scientific/technical implications)
In collaboration with the UKE institutional technology transfer office, we assessed the freedom-to-operate and patentability landscape for microbiota-derived metabolites, focussing on 3-IAA and potential combinations. We concluded that freedom-to-operate was not a major barrier; however, patenting 3-IAA alone as a supplementation therapy would likely require developing and synthesising a slightly modified derivative with stronger novelty, which at present would entail substantial investment.
The initial recommendation to prioritise combinations (e.g. with SCFAs) was directly tested in preclinical studies, but the observed antagonistic effect of butyrate reduced the immediate patent attractiveness of that specific combination, and therefore no formal patent filing was pursued within ACT-PC. Nonetheless, this work advanced translational readiness by clarifying that future IP opportunities are more likely to lie in biomarker-based stratification claims and/or microbiota-engineering approaches to increase endogenous 3-IAA production.
Activity 4 — Market positioning (technical relevance to commercial landscape)
We reviewed the current treatment and business landscape to understand where a 3-IAA–based approach (and possibly other microbial metabolites) could fit in pancreatic cancer care and in the wider field of cancer therapy. This review suggested that the strongest case for further development is the combination of 3-IAA with other metabolites, in a combination never done before and with the use of 3-IAA concentration levels in the blood as a biomarker to identify who is most likely to respond.
Activity 5 — Business positioning (routes grounded in scientific outcomes)
We pulled together our technical and feasibility findings into clear development and exploitation options using a Business Model Canvas approach. This showed that developing a modified 3-IAA compound and producing it under GMP conditions is currently too expensive for an early-stage academic program. We therefore defined three practical and complementary alternatives: (1) develop microbiota-based approaches (engineering/evolution) to boost the body’s own 3-IAA production, (2) pursue partnerships or licensing with biotech/pharma companies that have the required development infrastructure, and (3) develop a diagnostic/stratification route that uses blood 3-IAA levels as a biomarker to help identify patients who are more likely to respond to chemotherapy.
We gathered further evidence supporting the potential therapeutic use of 3-IAA. In mouse studies, we confirmed that 3-IAA can enhance chemotherapy efficacy, but we also found that butyrate may reduce this benefit in the model tested, showing that combining seemingly “helpful” metabolites is not always straightforward.
Next steps include evaluating 3-IAA as a blood-based biomarker of treatment response, understanding why butyrate counteracts its effect, and testing other metabolites and combinations. Since clinical-grade 3-IAA is currently expensive to produce, a promising alternative is to boost 3-IAA naturally through selected gut bacteria, or to partner with organisations that can support manufacturing and clinical testing.
Next steps include evaluating 3-IAA as a blood-based biomarker of treatment response, understanding why butyrate counteracts its effect, and testing other metabolites and combinations. Since clinical-grade 3-IAA is currently expensive to produce, a promising alternative is to boost 3-IAA naturally through selected gut bacteria, or to partner with organisations that can support manufacturing and clinical testing.