In a study published in the Journal of Experimental Medicine, Taconic models engrafted with patient-derived xenografts (PDX) demonstrated that mitoribosome-targeting antibiotics may have a role in treating melanoma.
Despite significant advances in oncology research, tumor resistance to therapy remains a major challenge. Immune checkpoint inhibitors (ICIs) like pembrolizumab and nivolumab exhibit a wide disparity between responders and non-responders, which has prompted investigators to explore various avenues to improve cancer therapy efficacy. One such approach is repurposing approved drugs (such as antibiotics) for use in oncology applications.
Given the high rate of failure at the clinical stage and the lengthy timeline to bring a new compound to market, repurposing therapeutics previously approved by regulatory bodies for secondary applications can de-risk and speed up the drug development process to address oncology treatment challenges. In a recent study that explored this strategy, researchers used several Taconic models to test the viability of repurposing mitoribosome-targeting antibiotics as anti-cancer therapies, especially in melanoma tumors previously resistant to targeted therapy or immunotherapy.
Since both DTP cells and the ISR are dependent on mitochondrial biology, investigators have asked whether it's possible to exploit this vulnerability by treating cancer patients with antibiotics that inhibit mitochondrial protein synthesis. Tigecycline, part of the tetracycline family of antibiotics, is one compound shown to inhibit the action of mitoribosomes in hematologic cancers.
In a paper published in the Journal of Experimental Medicine, co-authored by Taconic Field Applications Scientist Ivan Gladwyn-Ng, PhD, researchers studied the potential for mitochondrial protein synthesis impairment to inhibit the development of metastatic melanoma tumor resistance. One of the study's primary objectives was to identify vulnerabilities in melanoma resulting from a mutation in the BRAF gene and to determine if mitoribosome-targeting antibiotics could exploit those vulnerabilities to prevent or delay the onset of melanoma resistance to therapy.
The huNOG-EXL expresses human GM-CSF (granulocyte-macrophage colony-stimulating factor) and human interleukin 3 (IL-3) cytokines which support reconstitution of human myeloid lineages following engraftment with human hematopoietic stem cells (HSCs). Myeloid cells are known to play a role in the innate immune response. Combinatorial immuno-oncology therapeutic strategies target the ISR which is increasingly recognized as a critical determinant of tumorigenesis and demonstrated to be upregulated in many cancers. ISR can be triggered by cell-intrinsic and cell-extrinsic conditions, and can influence multiple downstream signaling pathways, several of which have been identified to modulate innate immune mediators. Since this model supports high engraftment levels of human immune cells, including both lymphoid and myeloid cell differentiation, the huNOG-EXL is ideal for oncology research applications exploring the role of immune-modulating therapies.
"Multiple research groups from both academia & biopharmaceutical industry have successfully utilized the huNOG-EXL in their immuno-oncology drug development programs. Our collaboration with Prof. Leucci's group in KU Leuven is one example how researchers hope to improve the therapeutic strategies for cancer" said Gladwyn-Ng.
The NMRI nude was engrafted with patient-derived tumors to develop multiple melanoma PDX models that were treated with tigecycline during the study. One such melanoma PDX model (Mel-006) was then engrafted onto the huNOG-EXL to test antibiotic treatment in combination with immunotherapy.
While mice in both cohorts initially responded to DT, then developed resistance, the addition of the antibiotic delayed or prevented resistance to the targeted therapy in both models.
Additionally, the researchers explored whether tumors previously unresponsive to immunotherapy might be sensitive to the inhibition of mitochondrial translation. To assess how the addition of tigecycline might impact immunotherapy, Mel-006 was engrafted onto the Taconic huNOG-EXL HIS model, then treated with the anti-PD-1 nivolumab, either with or without tigecycline. The antibiotic treatment neither enhanced nor impaired the immunotherapy. So while tigecycline did not sensitize the model to the ICI, its use as monotherapy proved efficacious in significantly delaying the progression of melanoma lesions previously found to be resistant to immunotherapy.
"The combined in vivo findings with in vitro results identified Activating Transcription Factor 4 (ATF-4) as a novel predictive biomarker to augment the current standard-of-care for melanoma patients and for improved patient stratification for this drug-repurposing combinational strategy," Gladwyn-Ng said.
The ability to repurpose approved, widely used drugs to treat patients whose tumors are resistant to immunotherapy or targeted therapy has the potential to speed efficacious treatments to the clinic, either as an alternative monotherapy or in combination with other therapeutics. Mouse models will continue to play an important role in testing these approaches and helping physicians provide promising options to non-responder patients.
Ivan Gladwyn-Ng (B.Sc.(Med.), PhD, is a Field Applications Scientist at Taconic Biosciences who has utilized rodent models within many diverse fields of preclinical research for more than a decade. He is passionate about accelerating advancements in human health by improving the care and application of in vivo animal models in the drug discovery process. He is particularly interested in the studies of infectious, oncological, metabolic, and neurological diseases. Ivan has led multi-disciplinary research teams with global collaborations in laboratories from diverse parts of the world, as adjunct researcher and post-doctoral research fellow in the Institut Pasteur (Paris, France), Harry Perkins Institute of Medical Research (Perth, Australia), and the GIGA Institute (Liege, Belgium) with successful co-first and corresponding authorships in Nature Research, Cell Press, Science and Frontiers publications as well as successful patent applications in Europe and USA. Prior to these, he was conferred his doctorate at the Australian Regenerative Medicine Institute (Melbourne, Australia), after completing the sale of his start-up company, with First-Class Honours (top student) after completing his undergraduate studies (B.Sc. (Med.) at Monash University.
Despite significant advances in oncology research, tumor resistance to therapy remains a major challenge. Immune checkpoint inhibitors (ICIs) like pembrolizumab and nivolumab exhibit a wide disparity between responders and non-responders, which has prompted investigators to explore various avenues to improve cancer therapy efficacy. One such approach is repurposing approved drugs (such as antibiotics) for use in oncology applications.
Given the high rate of failure at the clinical stage and the lengthy timeline to bring a new compound to market, repurposing therapeutics previously approved by regulatory bodies for secondary applications can de-risk and speed up the drug development process to address oncology treatment challenges. In a recent study that explored this strategy, researchers used several Taconic models to test the viability of repurposing mitoribosome-targeting antibiotics as anti-cancer therapies, especially in melanoma tumors previously resistant to targeted therapy or immunotherapy.
The Mechanisms of Tumor Resistance
In some instances, tumors are able to evolve and develop drug resistance when faced with environmental stressors such as therapeutics. One reason for the development of resistance is the ability for a subset of cancer cells, known as drug-tolerant persister (DTP) cells, to engage adaptation programs that result in drug-tolerant phenotypes. The integrated stress response (ISR) is also known to improve tumor survival by coordinating various cellular responses that enable cancer cells to adapt to stress and continue to proliferate.Since both DTP cells and the ISR are dependent on mitochondrial biology, investigators have asked whether it's possible to exploit this vulnerability by treating cancer patients with antibiotics that inhibit mitochondrial protein synthesis. Tigecycline, part of the tetracycline family of antibiotics, is one compound shown to inhibit the action of mitoribosomes in hematologic cancers.
In a paper published in the Journal of Experimental Medicine, co-authored by Taconic Field Applications Scientist Ivan Gladwyn-Ng, PhD, researchers studied the potential for mitochondrial protein synthesis impairment to inhibit the development of metastatic melanoma tumor resistance. One of the study's primary objectives was to identify vulnerabilities in melanoma resulting from a mutation in the BRAF gene and to determine if mitoribosome-targeting antibiotics could exploit those vulnerabilities to prevent or delay the onset of melanoma resistance to therapy.
Leveraging PDX and Humanized Models
The study employed two mouse models from Taconic: the NMRI nude immunodeficient model, widely used for transplantation of human tumors, and the huNOG-EXL, a humanized immune system (HIS) model that is widely utilized in human patient PDX studies.The huNOG-EXL expresses human GM-CSF (granulocyte-macrophage colony-stimulating factor) and human interleukin 3 (IL-3) cytokines which support reconstitution of human myeloid lineages following engraftment with human hematopoietic stem cells (HSCs). Myeloid cells are known to play a role in the innate immune response. Combinatorial immuno-oncology therapeutic strategies target the ISR which is increasingly recognized as a critical determinant of tumorigenesis and demonstrated to be upregulated in many cancers. ISR can be triggered by cell-intrinsic and cell-extrinsic conditions, and can influence multiple downstream signaling pathways, several of which have been identified to modulate innate immune mediators. Since this model supports high engraftment levels of human immune cells, including both lymphoid and myeloid cell differentiation, the huNOG-EXL is ideal for oncology research applications exploring the role of immune-modulating therapies.
"Multiple research groups from both academia & biopharmaceutical industry have successfully utilized the huNOG-EXL in their immuno-oncology drug development programs. Our collaboration with Prof. Leucci's group in KU Leuven is one example how researchers hope to improve the therapeutic strategies for cancer" said Gladwyn-Ng.
The NMRI nude was engrafted with patient-derived tumors to develop multiple melanoma PDX models that were treated with tigecycline during the study. One such melanoma PDX model (Mel-006) was then engrafted onto the huNOG-EXL to test antibiotic treatment in combination with immunotherapy.
A Novel Approach to Inhibiting Tumor Resistance Development
The researchers used two BRAFv6000E PDX models (Mel-015 and Mel-006) to investigate whether the use of the antibiotic tigecycline, alone or in combination with dabrafenib + trametinib (DT), the standard of care for metastatic melanoma, would impact the onset of tumor resistance.While mice in both cohorts initially responded to DT, then developed resistance, the addition of the antibiotic delayed or prevented resistance to the targeted therapy in both models.
- In the Mel-015 cohort of mice, administration of tigecycline at the start of DT treatment or after lesions reached minimal residual disease significantly delayed the onset of resistance development and increased both progression-free survival and overall survival.
- In the Mel-006 cohort, concurrent treatment with DT and tigecycline resulted in tumor remission in 11 of the 14 mice.
Additionally, the researchers explored whether tumors previously unresponsive to immunotherapy might be sensitive to the inhibition of mitochondrial translation. To assess how the addition of tigecycline might impact immunotherapy, Mel-006 was engrafted onto the Taconic huNOG-EXL HIS model, then treated with the anti-PD-1 nivolumab, either with or without tigecycline. The antibiotic treatment neither enhanced nor impaired the immunotherapy. So while tigecycline did not sensitize the model to the ICI, its use as monotherapy proved efficacious in significantly delaying the progression of melanoma lesions previously found to be resistant to immunotherapy.
"The combined in vivo findings with in vitro results identified Activating Transcription Factor 4 (ATF-4) as a novel predictive biomarker to augment the current standard-of-care for melanoma patients and for improved patient stratification for this drug-repurposing combinational strategy," Gladwyn-Ng said.
The ability to repurpose approved, widely used drugs to treat patients whose tumors are resistant to immunotherapy or targeted therapy has the potential to speed efficacious treatments to the clinic, either as an alternative monotherapy or in combination with other therapeutics. Mouse models will continue to play an important role in testing these approaches and helping physicians provide promising options to non-responder patients.
Ivan Gladwyn-Ng (B.Sc.(Med.), PhD, is a Field Applications Scientist at Taconic Biosciences who has utilized rodent models within many diverse fields of preclinical research for more than a decade. He is passionate about accelerating advancements in human health by improving the care and application of in vivo animal models in the drug discovery process. He is particularly interested in the studies of infectious, oncological, metabolic, and neurological diseases. Ivan has led multi-disciplinary research teams with global collaborations in laboratories from diverse parts of the world, as adjunct researcher and post-doctoral research fellow in the Institut Pasteur (Paris, France), Harry Perkins Institute of Medical Research (Perth, Australia), and the GIGA Institute (Liege, Belgium) with successful co-first and corresponding authorships in Nature Research, Cell Press, Science and Frontiers publications as well as successful patent applications in Europe and USA. Prior to these, he was conferred his doctorate at the Australian Regenerative Medicine Institute (Melbourne, Australia), after completing the sale of his start-up company, with First-Class Honours (top student) after completing his undergraduate studies (B.Sc. (Med.) at Monash University.