Biology subjects

Bukhari, A. B.

Publications and source records attributed to Bukhari, A. B..

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↗

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↗

bioRxiv2017

Soft drug-resistant ovarian cancer cells invade via two distinct mechanisms utilizing myosin IIB

The failure of chemotherapeutic drugs in treatment of various cancers is attributed to the acquisition of drug resistance. However, the invasion mechanisms of drug-resistant cancer cells remains incompletely understood. Here we address this question from a biophysical perspective by mapping the phenotypic alterations in ovarian cancer cells (OCCs) resistant to cisplatin and paclitaxel. We show that cisplatin-resistant (CisR), paclitaxel-resistant (PacR) and dual drug-resistant (i.e., resistant to both drugs) OCCs are softer and more contractile than drug-sensitive cells. Protease inhibition suppresses invasion of CisR cells but not of PacR and dual cells, suggesting protease-dependent mode of invasion in CisR cells and protease-independent mode in PacR and dual cells. Despite these differences, actomyosin contractility, mediated by the RhoA-ROCK2-Myosin IIB signaling pathway regulates both modes of invasion. Myosin IIB modulates matrix metalloproteinase-9 (MMP-9) secretion in CisR cells and nuclear squeezing in PacR and dual cells, thereby highlighting its importance as a potential therapeutic target for treatment of drug-resistant ovarian cancer cells.\n\nFinancial SupportAuthors acknowledge financial support from IIT Bombay Healthcare Initiative, CSIR andDepartment of Biotechnology (Govt. of India) (Grant # BT/PR14658/MED/31/107/2010).AK and BTwere supported by fellowships from UGC and CSIR respectively (Govt. of India).\n\nAuthors declare no competing financial interests\n\nAuthor contributions: AK, PR and SS designed the experiments. AK performed most of the experiments and analyzed the data.BT and SG developed drug resistant cell lines and did RT-PCR. MM performed western blot. AD performed AFM experiments. SD performed gelatin zymography. ABB, PM, AM and AD helped with live cell imaging experiments. AK and SS wrote the manuscript. All authors read and approved the final manuscript.\n\nSummary statement: This study identifies drug-specific differences in the modes of invasion utilized by ovarian cancer cells, and demonstrates the role of myosin IIB in regulating both modes of invasion.

biophysics↗