Biology subjects

Gamper, A. M.

Publications and source records attributed to Gamper, A. M..

3 recordsLinked to original sources

bioRxiv2026

FLT-PET as predictive non-invasive biomarker for neoadjuvant therapy with Wee1 and ATR inhibitors

Besides immunotherapy, inhibitors of the DNA damage response (DDR) are currently one of the most promising contributors to improved cancer therapy. They exploit elevated replicative stress in cancer cells and often rely on synthetic lethality with existing gene deficiencies or between targeted pathways. In view of the absence of reliable histological biomarkers for replicative stress, this study examined [18F]-fluorothymidine (FLT) positron emission tomography (PET) as alternative or complementary approach to predict treatment response to DDR inhibitors. Using orthotopic and syngeneic triple negative breast cancer mouse models and treatment with combined AZD6738 and AZD1775 (inhibiting ATR and Wee1, respectively) this study found that: a) Sequential [18F]FLT-PET in the early phase of treatment was able to predict ATR/Wee1 inhibitor treatment efficacy, whereas b) [18F]FLT tumor uptake at onset of therapy was unable to predict treatment outcome, despite c) [18F]FLT tumor uptake positively correlating with Ki-67 staining, the clinically used proliferation marker. Importantly, non-invasive monitoring of changes in tumor biology by [18F]FLT-PET predicted which tumor model responds to combined AZD6738/AZD1775 treatment and established a quantitative correlation in [18F]FLT tumor uptake with tumor shrinkage in individual responders. Since the inhibitors AZD6738 and AZD1775 are already in phase I/II clinical trials, this knowledge could soon be translated into the clinic. To our knowledge this is the first study to correlate non-invasive PET imaging with treatment efficacy of DDR inhibitors. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=100 SRC="FIGDIR/small/710900v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@1e18b7eorg.highwire.dtl.DTLVardef@8d306corg.highwire.dtl.DTLVardef@1663a21org.highwire.dtl.DTLVardef@7261c2_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

Mechanistic insights into transcriptional regulation of ARHGAP36 expression identify a factor predictive of neuroblastoma survival

Cancer repeatedly exploits attributes fundamental for morphogenesis to advance malignancy and metastasis. This is illustrated by lineage specific transcription factors that regulate neural crest migration representing frequent drivers of malignancy. One such example is the forkhead transcription factor FOXC1 where gain of function is a feature of diverse cancers that is associated with an unfavourable prognosis. Using RNA-, ChIP-sequencing and CRISPR interference, we show that Foxc1 binds a locus in a region of closed chromatin to induce expression of Arhgap36, a tissue-specific inhibitor of Protein Kinase A. Because PKA is a core Hedgehog (Hh) pathway inhibitor, Foxc1s induction of Arhgap36 expression increases Hh activity. The function of Sufu, a PKA substrate and a second essential Hh pathway inhibitor, is likewise impaired. The resulting increased Hh pathway output is resistant to pharmacological inhibition of Smoothened, a phenotype of more aggressive cancers. The Foxc1-Arhgap36 relationship identified in murine cells was further evaluated in neuroblastoma, a neural crest derived pediatric malignancy. This demonstrated in a cohort of 1348 patients that high levels of ARHGAP36 are predictive of improved five-year survival. Accordingly, this study has identified as a novel transcription factor which enhances ARHGAP36 expression, one that induces Hh activity in multiple tissues during development. It also establishes a model by which increased levels of FOXC1 via ARHGAP36 and PKA inhibition dysregulate multiple facets of Hh signaling, and provides evidence demonstrating relevance to a common neural-crest derived malignancy.

molecular biology↗

bioRxiv2020

Docosahexaenoic acid significantly reduces tumor cell growth in preclinical models of ovarian cancer

Despite recent advances in diagnosis and treatment, ovarian cancer (OC) is the most lethal gynecological malignancy and improving the efficacy of chemotherapy is of great interest. This study increases our understanding of how dietary intervention with docosahexaenoic acid (DHA)-a supplement proven safe for human consumption - enhances the anti-cancer effects of conventional chemotherapy. Our results demonstrated synergistic cell killing by DHA and carboplatin in OC cell lines. Furthermore, DHA supplementation alone and in combination with carboplatin significantly reduced OC growth in a high-grade serous OC patient-derived xenograft mouse model. Carboplatin administered intraperitoneally significantly reduced tumor growth in DHA-fed mice compared to mice on the control diet. Intravenous carboplatin administration in combination with DHA reduced tumor growth similarly to carboplatin or DHA monotherapies. The DHA-induced reduction in tumor growth in this model was associated with increased tumor necrosis and improved survival. As such, our findings provide a strong rationale to move to clinical trials that will determine whether DHA supplementation enhances the efficacy and tolerance of cytotoxic chemotherapy in patients with OC.

cancer biology↗