Targeting the inflammatory response in advanced prostate cancer
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Date
2024-05-20ICR Author
Author
De Bono J
Guo, WY
De Bono, J
Type
Thesis or Dissertation
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Prostate cancer is a leading cause of male cancer mortality. Despite inflammation being implicated in prostate cancer initiation and progression, patient outcomes have been minimally impacted by immunotherapies that have imparted durable benefit in other advanced malignancies. There is an unmet need to elucidate the inflammatory response and develop novel immunotherapies for patients with prostate cancer.
In this thesis, I first investigated the expression, function, and therapeutic targeting of B7-H3, a member of the B7 family of immunomodulatory proteins, against which therapeutic antibodies, antibody-drug conjugates (ADCs), and cellular therapies are being developed. This investigation revealed that, in contrast to PD-L1 (B7-H1), which is infrequently expressed by prostate cancer cells, another member of this family B7-H3 is among the most highly expressed immunomodulatory molecules in castration-resistant prostate cancer (CRPC). B7-H3 expression was higher in tumours with pathogenic DNA damage response (DDR) gene alterations and inversely associated with the infiltration of T lymphocyte in tumour. Targeting B7-H3 in human prostate cancer cell lines, organoids, and xenografts led to B7-H3 dependent tumour cell kill. However, in vivo studies demonstrated incomplete tumour eradication, with residual B7-H3 positive cells exhibiting features of cellular senescence across all treatment-responsive models.
Tumour cell senescence, regardless of trigger, has been linked to secretory phenotypes that include chemotactic (and other) cytokines which attract pathogenic myeloid cells known to cause therapy resistance in prostate cancer mouse models. Therefore, I conducted translational and clinical studies elucidating the relationship between senescence and myeloid inflammation in patients with mCRPC. Peripheral blood and intratumour myeloid expansion correlated, with both also associating with tumour expression of senescence-associated, and negatively prognostic Glu-Leu-Arg (ELR+) CXC chemokines (named for their N-terminal glutamate, leucine, and arginine tripeptide motif preceding the C-X-C chemokine motif) that bind CXCR1 and CXCR2. CXCR2 was selectively expressed by myeloid cells in CRPC. The availability of selective and potent CXCR2 inhibitor (CXCR2i) developed to treat inflammatory non-malignant indications, allowed for further clinical investigations of this target. In an investigator-initiated, proof-of-concept, proof-of-mechanism, phase-1 trial combining a CXCR2i with enzalutamide in patients with CRPC, I showed that this combination led to dose-dependent decreases in peripheral blood neutrophils, reduced myeloid cell infiltration in some CRPC biopsies, and conferred clinical antitumour activity in some patients. Taken together, these results indicate that a senescence-associated inflammatory milieu may signal via the CXCR1/2 axis to recruit myeloid cells, with inhibition of this axis causing tumour shrinkage supporting the pathogenic role of myeloid inflammation in CRPC. A second clinical trial targeting the myeloid paracrine factor, IL-23, shown to drive AR signalling through the RORγ-JAK2-STAT3 axis was initiated but terminated by the study’s funder SUN Pharma before completion for strategic reasons after limited antitumour activity was demonstrated in a small dose escalation clinical trial.
In summary, I provided insights into the inflammatory response in CRPC and demonstrated novel immunotherapeutic approaches for its management.
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Research team
PrCa Targeted Therapy
Language
eng
License start date
2024-05-20
Citation
2024
Publisher
Institute of Cancer Research (University Of London)