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Microbes & Immunity The feature of bladder cancer stem cells

remains ample room for optimization in BCMab1 vs. 53 days). Taken together, chaetocin, as an effective
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therapy. First, BCMab1 needs to be humanized to mitigate inhibitor targeting KMT1A, holds promising potential as
potential immunogenicity concerns. Second, large-scale a treatment strategy for BC.
clinical trials of BCMab1-Ra are warranted to verify its The Hedgehog pathway transports Gli proteins into
reproducibility. Third, the efficacy of BCMab1-Ra should the cell nucleus, leading to the upregulation of Hedgehog
be further evaluated in the patient-derived xenograft target genes. Despite the initial favorable response, patients
mouse model to provide additional insights into its treated with SMO antagonists have eventually developed
effectiveness. However, BCMab1-Ra still holds enormous resistance due to the occurrence of compensating
potential in the treatment of BC.
mechanisms. 120,121 A novel SMO inhibitor, taladegib,
3.8.2. Inhibitors of signaling pathways has demonstrated the ability to reduce the proliferation
of Hedgehog-driven murine medulloblastoma.
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STAT3 not only serves as the key factor of self-renewal Importantly, taladegib binds to vismodegib-resistant
of BCSCs but also drives the suppression of anti-tumor SMO, helping to overcome acquired drug resistance.
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immune response, rendering it a versatile target in On the other hand, ATO; glabrescione B; and HPI-1,
oncology. Consequently, inhibitors targeting STAT3 HPI-2, HPI-3, and HPI-4 have been reported to inhibit
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have been extensively researched for decades, with many Gli1 protein in mouse models. 124-126 In the BC indication,
undergoing clinical trials for liver cancer, colorectal researchers led by Lihong Zhu from the Institute of Plant
cancer, and leukemia (NCT03382340, NCT02983578, Protection and Microbiology at Zhejiang Academy of
NCT02993731, respectively). As phosphorylation induces Agricultural Sciences isolated a novel Hedgehog inhibitor
dimerization of STAT3 proteins, the majority of research called iG2 from the bacterium Roseofilum. This inhibitor
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efforts have focused on inhibiting this dimerization significantly blocks the activation of Gli2 in BC cells. The
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process. Notably, a recent Phase III monotherapy trial results indicated that iG2 could weaken the proliferative
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revealed the excellent anti-tumor efficacy of BBI068 (a capacity, self-renewal ability, and tumor-forming capability
STAT3 inhibitor) in patients with advanced colorectal of BC cells. It exhibited a dose-dependent effect, with the
cancer patients who tested positive for phosphorylated IC usually being higher for stromal cells surrounding
50
STAT3, compared to placebo. Due to the high sequence the tumor compared to tumor cells themselves. iG2
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similarity within the STAT family, small molecular also demonstrated good tolerability in mouse models,
inhibitors must exhibit high specificity. Furthermore, suggesting potential for future clinical applications. 127
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gene therapy utilizing small interference RNA (siRNA)
has presented prominent specificity and lower toxicity However, resistance to monotherapy is inevitable. In
in preclinical experiments. 115,116 However, challenges the future, combining Gli inhibitor with SMO inhibitor
such as the instability, deficiency of efficient targeted may be a promising way to overcome drug resistance and
delivery vectors, and the immunogenicity of RNA have potentially achieve enhanced effects in BC therapy.
hindered the translation of siRNA-based therapies into
clinical applications. Future advancements in optimized 3.8.3. CD47
+
delivery vectors and RNA design hold huge potential for CD47 expression levels are significantly higher in CD44
-
clinical translation. In addition, proteolysis-targeting BCSCs compared to CD44 BCNSCs. CD47 primarily
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chimera (PROTAC) has been demonstrated to induce the functions by binding to signal regulatory protein alpha
degradation of STAT3 and prove to be an efficient approach (SIRPα) expressed on phagocytic cells, sending a “Don’t
in leukemia and lymphoma mouse models. Given the Eat Me” signal, and inhibiting the phagocytic activity of
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important role of STAT3 in the stemness and progression macrophages. This mechanism protects BCSCs from being
of BC, the promising effects observed by targeting STAT3 engulfed by immune cells. 27
are likely applicable to BC patients as well. Chan et al. co-cultured BC cells derived from BC
Recently, our group has discovered that chaetocin, a samples with mouse macrophages. They found that adding
KMT1A inhibitor, significantly inhibited the proliferation antibodies blocking CD47 resulted in a phagocytic index
of BC cells (inhibition rate: 65 – 88%, IC 24.4 – 32.5 nM), at least twice as high as the other two groups, promoting
50:
induced apoptosis (2 – 5 folds increase), and caused G1 phase the engulfment of BC cells by macrophages. In contrast,
cell cycle arrest in BC cells (68.9% versus 55.5%), without using IgG1 isotype antibodies or mouse anti-human HLA
affecting normal bladder epithelial cells. Furthermore, antibodies did not significantly enhance phagocytosis,
27
intravesical injection of chaetocin significantly inhibited suggesting the potential therapeutic value of CD47. In
the growth of xenograft tumors (inhibition rate: 71 – 82%) addition, researchers led by Stephen B. Willingham from
and prolonged the survival of tumor-bearing mice (70 days Stanford University investigated CD47 using metastatic

Volume 1 Issue 1 (2024) 40 doi: 10.36922/mi.2377