ORCID Profile
0000-0002-2354-3521
Current Organisations
Central Adelaide Local Health Network
,
University of South Australia
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: American Association for Cancer Research (AACR)
Date: 15-05-2009
DOI: 10.1158/1078-0432.CCR-08-1616
Abstract: Purpose: To evaluate the efficacy of zoledronic acid (ZOL) against osteosarcoma (OS) growth, progression, and metastatic spread using an animal model of human OS that closely resembles the human disease. Experimental Design: Human K-HOS or KRIB OS cells, tagged or untagged with a luciferase reporter construct, were transplanted directly into the tibial cavity of nude mice. ZOL was given as weekly, or a single dose of 100 μg/kg body weight, equivalent to the 4 mg i.v. dose used clinically. Tumor growth at the primary site and as pulmonary metastases was monitored by bioluminescence imaging and histology, and OS-induced bone destruction was measured using high-resolution micro–computed tomography. Results: Mice transplanted with OS cells exhibited aberrant bone remodeling in the area of cancer cell transplantation, with areas of osteolysis mixed with extensive new bone formation extending from the cortex. ZOL administration prevented osteolysis and significantly reduced the amount of OS-induced bone formation. However, ZOL had no effect on tumor burden at the primary site. Importantly, ZOL failed to reduce lung metastasis and in some cases was associated with larger and more numerous metastatic lesions. Conclusions: Our data show that clinically relevant doses of ZOL, while protecting the bone from OS-induced bone destruction, do not inhibit primary tumor growth. Moreover, lung metastases were not reduced and may even have been promoted by this treatment, indicating that caution is required when the clinical application of the bisphosphonate class of antiresorptives is considered in OS.
Publisher: Elsevier BV
Date: 2017
DOI: 10.1016/J.MCE.2016.11.007
Abstract: Myeloperoxidase (MPO) and eosinophil peroxidase (EPO) are heme-containing enzymes, well known for their antimicrobial activity, are released in abundance by innate immune infiltrates at sites of inflammation and injury. We have discovered new and previously unrecognised roles for heme peroxidases in extracellular matrix biosynthesis, angiogenesis, and bone mineralisation, all of which play an essential role in skeletal integrity. In this study we used in vitro models of osteoclastogenesis to investigate the effects of heme peroxidase enzymes on osteoclast differentiation and bone resorbing activity, pertinent to skeletal development and remodelling. Receptor activator of nuclear factor kappa B-ligand (RANKL) stimulates the formation of tartate-resistant acid phosphatase (TRAP) positive multinucleated cells and increases bone resorption when cultured with human peripheral blood mononuclear cells (PBMCs) or the RAW264.7 murine monocytic cell line. When RANKL was added in combination with either MPO or EPO, a dose-dependent inhibition of osteoclast differentiation and bone resorption was observed. Notably, peroxidases had no effect on the bone resorbing activity of mature osteoclasts, suggesting that the inhibitory effect of the peroxidases was limited to osteoclast precursor cells. Mechanistically, we observed that osteoclast precursor cells readily internalize peroxidases, and inhibited the phosphorylation of JNK, p38 MAPK and ERK1/2, important signalling molecules central to osteoclastogenesis. Our findings suggest that peroxidase enzymes, like MPO and EPO, may play a fundamental role in inhibiting RANKL-induced osteoclast differentiation at inflammatory sites of bone fracture and injury. Therefore, peroxidase enzymes could be considered as potential therapeutic agents to treat osteolytic bone disease and aberrant bone resorption.
Publisher: Elsevier BV
Date: 11-2015
DOI: 10.1016/J.BIOCEL.2015.09.006
Abstract: Peroxidases are heme-containing enzymes released by activated immune cells at sites of inflammation. To-date their functional role in human health has mainly been limited to providing a mechanism for oxidative defence against invading bacteria and other pathogenic microorganisms. Our laboratory has recently identified a new functional role for peroxidase enzymes in stimulating fibroblast migration and collagen biosynthesis, offering a new insight into the causative association between inflammation and the pro-fibrogenic events that mediate tissue repair and regeneration. Peroxidases are found at elevated levels within and near blood vessels however, their direct involvement in angiogenesis has never been reported. Here we report for the first time that myeloperoxidase (MPO) and eosinophil peroxidase (EPO) are readily internalised by human umbilical vein endothelial cells (HUVEC) where they promote cellular proliferation, migration, invasion, and stimulate angiogenesis both in vitro and in vivo. These pro-angiogenic effects were attenuated using the specific peroxidase inhibitor 4-ABAH, indicating the enzyme's catalytic activity is essential in mediating this response. Mechanistically, we provide evidence that MPO and EPO regulate endothelial FAK, Akt, p38 MAPK, ERK1/2 phosphorylation and stabilisation of HIF-2α, culminating in transcriptional regulation of key angiogenesis pathways. These findings uncover for the first time an important and previously unsuspected role for peroxidases as drivers of angiogenesis, and suggest that peroxidase inhibitors may have therapeutic potential for the treatment of angiogenesis related diseases driven by inflammation.
Publisher: Wiley
Date: 02-2010
DOI: 10.1002/IJC.25051
Publisher: Wiley
Date: 18-02-2011
DOI: 10.1002/JBMR.244
Publisher: Spandidos Publications
Date: 20-02-2017
Abstract: Myeloperoxidase (MPO) and eosinophil peroxidase (EPO) are heme-containing enzymes, well known for their antimicrobial activity, are released in high quantities by infiltrating immune cells in breast cancer. However, the functional importance of their presence within the tumour microenvironment is unclear. We have recently described a new role for peroxidases as key regulators of fibroblast and endothelial cell functionality. In the present study, we investigate for the first time, the ability of peroxidases to promote breast cancer development and progression. Using the 4T1 syngeneic murine orthotopic breast cancer model, we examined whether increased levels of peroxidases in developing mammary tumours influences primary tumour growth and metastasis. We showed that MPO and EPO stimulation increased mammary tumour growth and enhanced lung metastases, effects that were associated with reduced tumour necrosis, increased collagen deposition and neo-vascularisation within the primary tumour. In vitro, peroxidase treatment, robustly stimulated human mammary fibroblast migration and collagen type I and type VI secretion. Mechanistically, peroxidases induced the transcription of pro-tumorigenic and metastatic MMP1, MMP3 and COX-2 genes. Taken together, these findings identify peroxidases as key contributors to cancer progression by augmenting pro-tumorigenic collagen production and angiogenesis. Importantly, this identifies inflammatory peroxidases as therapeutic targets in breast cancer therapy.
Publisher: Springer Science and Business Media LLC
Date: 25-10-2023
Publisher: Elsevier BV
Date: 07-2022
DOI: 10.1016/J.BIOPHA.2022.113090
Abstract: The Fc region of a monoclonal antibody (mAb) can play a crucial role in its biodistribution and therapeutic activity. The chimeric mAb, chDAB4 (APOMAB®), which binds to dead tumor cells after DNA-damaging anticancer treatment, has been studied pre-clinically in both diagnostic and therapeutic applications in cancer. Given that macrophages contribute to the tumor accumulation of chDAB4 and its potency as an antibody drug conjugate in vivo, we next wanted to determine whether the Fc region of the chDAB4 mAb also contributed. We found that, regardless of prior labeling with chDAB4, dead EL4 lymphoma or Lewis Lung (LL2) tumor cells were phagocytosed equally by wild-type or Fcγ knock-down macrophage cell lines. A similar result was seen with bone marrow-derived macrophages from wild-type, Fcγ knock-out (KO) and NOTAM mice that express Fcγ but lack immunoreceptor tyrosine-based activation motif (ITAM) signaling. Among EL4 tumor-bearing wild-type, Fcγ KO or NOTAM mice, no differences were observed in post-chemotherapy uptake of
Publisher: Springer Science and Business Media LLC
Date: 06-07-2021
DOI: 10.1007/S11307-021-01620-1
Abstract: Early detection of tumor treatment responses represents an unmet clinical need with no approved noninvasive methods. DAB4, or its chimeric derivative, chDAB4 (APOMAB®) is an antibody that targets the Lupus associated antigen (La/SSB). La/SSB is over-expressed in malignancy and selectively targeted by chDAB4 in cancer cells dying from DNA-damaging treatment. Therefore, chDAB4 is a unique diagnostic tool that detects dead cancer cells and thus could distinguish between treatment responsive and nonresponsive patients. In clinically relevant tumor models, mice bearing subcutaneous xenografts of human ovarian or lung cancer cell lines or intraperitoneal ovarian cancer xenografts were untreated or given chemotherapy followed 24h later by chDAB4 radiolabeled with [ 89 Zr]Zr IV . Tumor responses were monitored using bioluminescence imaging and caliper measurements. [ 89 Zr]Zr-chDAB4 uptake in tumor and normal tissues was measured using an Albira SI Positron-Emission Tomography (PET) imager and its biodistribution was measured using a Hidex gamma-counter. Tumor uptake of [ 89 Zr]Zr-chDAB4 was detected in untreated mice, and uptake significantly increased in both human lung and ovarian tumors after chemotherapy, but not in normal tissues. Given that tumors, rather than normal tissues, were targeted after chemotherapy, these results support the clinical development of chDAB4 as a radiodiagnostic imaging agent and as a potential predictive marker of treatment response.
Publisher: BMJ
Date: 03-2023
Abstract: Emerging evidence suggests that the mechanism of chemotherapy-induced cell death may influence the antitumor immune response in patients with cancer. Unlike immunologically silent apoptosis, pyroptosis is a lytic and inflammatory form of programmed cell death characterized by pore formation in the cell membrane and release of proinflammatory factors. Gasdermin E (GSDME) has recently gained attention after cleavage of GSDME by certain chemotherapeutics has been shown to elicit pyroptosis. This study investigated the immunomodulatory effects of a mesothelin-targeting antibody drug conjugate (ADC) in mouse models of breast and colon cancer. The antitumor effects of the ADC were studied in EMT6 breast cancer and CT26 colon cancer syngeneic mouse models. The immunomodulatory effects of the ADC were assessed by analysis of tumor-infiltrating immune cells using flow cytometry. ADC mechanism of action was evaluated by morphology, biological assays, ADC-mediated cleavage of key effector proteins, and CRISPR/Cas9-mediated knockout (KO). Finally, the antitumor effect of ADC and Fms-like tyrosine kinase-3 ligand (Flt3L) combination therapy was evaluated in tumors expressing GSDME as well as in GSDME-silenced tumors. The data demonstrated that the ADC controlled tumor growth and stimulated anticancer immune responses. Investigation of the mechanism of action revealed that tubulysin, the cytotoxic payload of the ADC, induced cleavage of GSDME and elicited pyroptotic cell death in GSDME-expressing cells. Using GSDME KO, we showed that GSDME expression is critical for the effectiveness of the ADC as a monotherapy. Combining the ADC with Flt3L, a cytokine that expands dendritic cells in both lymphoid and non-lymphoid tissues, restored control of GSDME KO tumors. Together, these results show for the first time that tubulysin and a tubulysin containing ADC can elicit pyroptosis, and that this fiery cell death is critical for antitumor immunity and therapeutic response.
Publisher: Elsevier BV
Date: 02-2017
Publisher: Elsevier BV
Date: 04-2015
DOI: 10.1016/J.BIOMATERIALS.2014.12.008
Abstract: Here, we report a detailed and systematic approach for studying the in vitro nanotoxicity study of high aspect ratio (HAR) nanomaterials using anodic alumina nanotubes (AANTs) as a nanomaterial model. AANTs with bio-inert properties and tailored aspect ratios ranging from 7.8 to 63.3 were synthesized by an electrochemical pulse anodization process. Cytotoxicity studies were conducted with RAW 264.7 mouse macrophage cells and MDA-MB 231-TXSA human breast cancer cells through several toxicity parameters, including cell viability and morphology, pro-inflammatory response, mitochondrial depolarization, lysosomal membrane permeabilization (LMP), induction of autophagy and endoplasmic reticulum (ER) stress. The resulting toxicity patterns were cell-type dependent and strongly related with AANTs dose, length of time, and importantly the AR of AANTs. Long AANTs triggered enhanced cell death, morphological changes, tumor necrosis factor α (TNF-α) release, LMP and ER stress than short AANTs. The toxic AR window of AANTs was determined to be 7.8, which is shorter than that of other previously reported HAR nanomaterials. This toxic AR window provides a promising opportunity to control the nanotoxicity of HAR nanomaterials for their advanced drug delivery application.
Publisher: American Association for Cancer Research (AACR)
Date: 02-2019
DOI: 10.1158/1535-7163.MCT-18-0842
Abstract: Antibody–drug conjugates (ADC) have revolutionized the field of cancer therapy. ADCs combine the high specificity of tumor-targeting monoclonal antibodies with potent cytotoxic drugs, which cannot be used alone because of their high toxicity. Till date, all ADCs have either targeted cell membrane proteins on tumors or the tumor vasculature and microenvironment. Here, we investigate ADCs of APOMAB (DAB4, or its chimeric derivative, chDAB4), which is a mAb targeting the La/SSB protein, which is only accessible for binding in dying or dead cancer cells. We show that DAB4-labeled dead cells are phagocytosed by macrophages, and that the apoptotic/necrotic areas within lung tumor xenografts are bound by DAB4 and are infiltrated with macrophages. We show that only DAB4–ADCs with a cleavable linker and diffusible drug are effective in two lung cancer models, particularly when given after chemotherapy. These results are consistent with other recent studies showing that direct internalization of ADCs by target cells is not essential for ADC activity because the linker can be cleaved extracellularly or through other mechanisms. Rather than targeting a tumor cell type specific antigen, DAB4–ADCs have the advantage of targeting a common trait in most solid tumors: an excess of post-apoptotic, necrotic cells either adjacent to hypoxic tumor regions or distributed more generally after cytotoxic therapy. Consequently, any antitumor effects are solely the result of bystander killing, either through internalization of the dead, ADC-bound tumor cells by macrophages, or extracellular cleavage of the ADC in the tumor microenvironment.
Publisher: American Association for Cancer Research (AACR)
Date: 15-05-2006
DOI: 10.1158/0008-5472.CAN-05-4386
Abstract: Breast cancer is the most common carcinoma that metastasizes to bone. To examine the efficacy of recombinant soluble Apo2 ligand (Apo2L)/tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) against breast cancer growth in bone, we established a mouse model in which MDA-MB-231 human breast cancer cells were transplanted directly into the marrow cavity of the tibiae of athymic nude mice producing osteolytic lesions in the area of injection. All vehicle-treated control animals developed large lesions that established in the marrow cavity, eroded the cortical bone, and invaded the surrounding soft tissue, as assessed by radiography, micro-computed tomography, and histology. In contrast, animals treated with recombinant soluble Apo2L/TRAIL showed significant conservation of the tibiae, with 85% reduction in osteolysis, 90% reduction in tumor burden, and no detectable soft tissue invasion. Tumor cells explanted from Apo2L/TRAIL–treated animals were significantly more resistant to the effects of Apo2L/TRAIL when compared with the cells explanted from the vehicle-treated control animals, suggesting that prolonged treatment with Apo2/TRAIL in vivo selects for a resistant phenotype. However, such resistance was readily reversed when Apo2L/TRAIL was used in combination with clinically relevant chemotherapeutic drugs, including taxol, etoposide, doxorubicin, cisplatin, or the histone deacetylase inhibitor suberoylanilide hydroxamic acid. These studies show for the first time that Apo2L/TRAIL can prevent breast cancer–induced bone destruction and highlight the potential of this ligand for the treatment of metastatic breast cancer in bone. (Cancer Res 2006 66(10): 5363-70)
Publisher: Wiley
Date: 10-08-2017
DOI: 10.1002/CAM4.1115
Publisher: Wiley
Date: 12-10-2021
DOI: 10.1002/CNR2.1543
Abstract: Platinum‐based chemotherapy and radiotherapy are standard treatments for non‐small cell lung cancer, which is the commonest, most lethal cancer worldwide. As a marker of treatment‐induced cancer cell death, we have developed a radiodiagnostic imaging antibody, which binds to La/SSB. La/SSB is an essential, ubiquitous ribonuclear protein, which is over expressed in cancer and plays a role in resistance to cancer therapies. In this study, we examined radiation‐induced DNA double strand breaks (DSB) in lung cancer cell lines and examined whether La/SSB associated with these DSB. Three lung cancer lines (A549, H460 and LL2) were irradiated with different X‐ray doses or X‐radiated with a 5 Gy dose and examined at different time‐points post‐irradiation for DNA DSB in the form of γ‐H2AX and Rad51 foci. Using fluorescence microscopy, we examined whether La/SSB and γ‐H2AX co‐localise and performed proximity ligation assay (PLA) and co‐immunoprecipitation to confirm the interaction of these proteins. We found that the radio‐resistant A549 cell line compared to the radio‐sensitive H460 cell line showed faster resolution of radiation‐induced γ‐H2AX foci over time. Conversely, we found more co‐localised γ‐H2AX and La/SSB foci by PLA in irradiated A549 cells. The co‐localisation of La/SSB with radiation‐induced DNA breaks suggests a role of La/SSB in DNA repair, however further experimentation is required to validate this.
Publisher: Elsevier BV
Date: 08-2012
DOI: 10.1016/J.BBRC.2012.07.053
Abstract: Indirubin derivatives gained interest in recent years for their anticancer and antimetastatic properties. The objective of the present study was to evaluate and compare the anticancer properties of the two novel bromo-substituted derivatives 6-bromoindirubin-3'-oxime (6BIO) and 7-bromoindirubin-3'-oxime (7BIO) in five different breast cancer cell lines. Cell viability assays identified that 6BIO and 7BIO are most effective in preventing the proliferation of the MDA-MB-231-TXSA breast cancer cell line from a total of five breast cancer cell lined examined. In addition it was found that the two compounds induce apoptosis via different mechanisms. 6BIO induces caspase-dependent programmed cell death through the intrinsic (mitochondrial) caspase-9 pathway. 7BIO up-regulates p21 and promotes G(2)/M cell cycle arrest which is subsequently followed by the activation of two different apoptotic pathways: (a) a pathway that involves the upregulation of DR4/DR5 and activation of caspase-8 and (b) a caspase independent pathway. In conclusion, this study provides important insights regarding the molecular pathways leading to cell cycle arrest and apoptosis by two indirubin derivatives that can find clinical applications in targeted cancer therapeutics.
Publisher: Wiley
Date: 2006
DOI: 10.1002/IJC.21939
Abstract: While the apoptosis-inducing ligand Apo2L/TRAIL is a promising new agent for the treatment of cancer, the sensitivity of cancer cells for induction of apoptosis by Apo2L/TRAIL varies considerably. Identification of agents that can be used in combination with Apo2L/TRAIL to enhance apoptosis in breast cancer cells would increase the potential utility of this agent as a breast cancer therapeutic. Here, we show that the histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), can sensitize Apo2L/TRAIL-resistant breast cancer cells to Apo2L/TRAIL-induced apoptosis. Importantly, neither Apo2L/TRAIL alone, nor in combination with SAHA, affected the viability of normal human cells in culture. Apo2L/TRAIL-resistant MDA-MB-231 breast cancer cells, generated by long-term culture in the continuous presence of Apo2L/TRAIL, were resensitized to Apo2L/TRAIL-induced apoptosis by SAHA. The sensitization of these cells by SAHA was accompanied by activation of caspase 8, caspase 9 and caspase 3 and was concomitant with Bid and PARP cleavage. The expression of the proapoptotic protein, Bax, increased significantly with SAHA treatment and high levels of Bax were maintained in the combined treatment with Apo2L/TRAIL. Treatment with SAHA increased cell surface expression of DR5 but not DR4. Interestingly, SAHA treatment also resulted in a significant increase in cell surface expression of DcR1. Taken together, our findings indicate that the use of these 2 agents in combination may be effective for the treatment of breast cancer.
Publisher: Springer Science and Business Media LLC
Date: 17-11-2020
DOI: 10.1186/S41181-020-00109-6
Abstract: The chimeric monoclonal antibody (mAb) chDAB4 (APOMAB®) targets the Lupus associated (La)/Sjögren Syndrome-B (SSB) antigen, which is over-expressed in tumors but only becomes available for antibody binding in dead tumor cells. Hence, chDAB4 may be used as a novel theranostic tool to distinguish between responders and nonresponders early after chemotherapy. Here, we aimed to ascertain which positron emitter, Zirconium-89 ([ 89 Zr]Zr IV ) or Iodine-124 ([ 124 I]I), was best suited to label chDAB4 for post-chemotherapy PET imaging of tumor-bearing mice and to determine which of two different bifunctional chelators provided optimal tumor imaging by PET using [ 89 Zr]Zr IV -labeled chDAB4. C57BL/6 J mice bearing subcutaneous syngeneic tumors of EL4 lymphoma were either untreated or given chemotherapy, then administered radiolabeled chDAB4 after 24 h with its biodistribution examined using PET and organ assay. We compared chDAB4 radiolabeled with [ 89 Zr] Zr IV or [ 124 I] I, or [ 89 Zr]Zr-chDAB4 using either DFO-NCS or DFOSq as a chelator. After chemotherapy, [ 89 Zr]Zr-chDAB4 showed higher and prolonged mean (± SD) tumor uptake of 29.5 ± 5.9 compared to 7.8 ± 1.2 for [ 124 I] I -chDAB4. In contrast, antibody uptake in healthy tissues was not affected. Compared to DFO-NCS, DFOSq did not result in significant differences in tumor uptake of [ 89 Zr]Zr-chDAB4 but did alter the tumor:liver ratio in treated mice 3 days after injection in favour of DFOSq (8.0 ± 1.1) compared to DFO-NCS (4.2 ± 0.7). ImmunoPET using chDAB4 radiolabeled with residualizing [ 89 Zr] Zr IV rather than [ 124 I] I optimized post-chemotherapy tumor uptake. Further, PET imaging characteristics were improved by DFOSq rather than DFO-NCS. Therefore, the radionuclide/chelator combination of [ 89 Zr] Zr IV and DFOSq is preferred for the imminent clinical evaluation of chDAB4 as a selective tumor cell death radioligand.
Publisher: American Association for Cancer Research (AACR)
Date: 10-2009
DOI: 10.1158/1535-7163.MCT-09-0745
Abstract: Apomab, a fully human agonistic DR5 monoclonal antibody, triggers apoptosis through activation of the extrinsic apoptotic signaling pathway. In this study, we assessed the cytotoxic effect of Apomab in vitro and evaluated its antitumor activity in murine models of breast cancer development and progression. MDA-MB-231-TXSA breast cancer cells were transplanted into the mammary fat pad or directly into the tibial marrow cavity of nude mice. Apomab was administered early, postcancer cell transplantation, or after tumors progressed to an advanced stage. Tumor burden was monitored progressively using bioluminescence imaging, and the development of breast cancer–induced osteolysis was measured using microcomputed tomography. In vitro, Apomab treatment induced apoptosis in a panel of breast cancer cell lines but was without effect on normal human primary osteoblasts, fibroblasts, or mammary epithelial cells. In vivo, Apomab exerted remarkable tumor suppressive activity leading to complete regression of well-advanced mammary tumors. All animals transplanted with breast cancer cells directly into their tibiae developed large osteolytic lesions that eroded the cortical bone. In contrast, treatment with Apomab following an early treatment protocol inhibited both intraosseous and extraosseous tumor growth and prevented breast cancer–induced osteolysis. In the delayed treatment protocol, Apomab treatment resulted in the complete regression of advanced tibial tumors with progressive restoration of both trabecular and cortical bone leading to full resolution of osteolytic lesions. Apomab represents a potent immunotherapeutic agent with strong activity against the development and progression of breast cancer and should be evaluated in patients with primary and metastatic disease. [Mol Cancer Ther 2009 (10):2969–80]
Publisher: Spandidos Publications
Date: 27-05-2014
Publisher: Elsevier BV
Date: 02-2014
Publisher: OMICS Publishing Group
Date: 2018
Publisher: Oxford University Press (OUP)
Date: 09-2018
DOI: 10.1093/ABT/TBY010
Abstract: Solid tumors are inherently difficult to treat because of large regions of hypoxia and are often chemotherapy- or radiotherapy-resistant. It seems that cancer stem cells reside in hypoxic and adjacent necrotic tumor areas. Therefore, new treatments that are highly selective for tumors and can eradicate cells in both hypoxic and necrotic tumor regions are desirable. Antibody α-radioconjugates couple an α-emitting radionuclide with the specificity of a tumor-targeting monoclonal antibody. The large mass and energy of α-particles result in radiation dose delivery within a smaller area independent of oxygen concentration, thus matching key criteria for killing hypoxic tumor cells. With advances in radionuclide production and chelation chemistry, α-radioconjugate therapy is regaining interest as a cancer therapy. Here, we will review current literature examining radioconjugate therapy specifically targeting necrotic and hypoxic tumor cells and outline how α-radioconjugate therapy could be used to treat tumor regions harboring more resistant cancer cell types. Statement of Significance Tumor-targeting antibodies are excellent vehicles for the delivery of toxic payloads directly to the tumor site. Tumor hypoxia and necrosis promote treatment recurrence, resistance, and metastasis. Targeting these areas with antibody α-radioconjugates would aid in overcoming treatment resistance.
Publisher: Springer Science and Business Media LLC
Date: 16-08-2021
Publisher: Elsevier BV
Date: 11-2020
Publisher: Wiley
Date: 09-01-2016
DOI: 10.1002/CAM4.599
Publisher: Research Square Platform LLC
Date: 03-06-2020
DOI: 10.21203/RS.3.RS-32059/V1
Abstract: Purpose. There are no currently approved non-invasive methods for detecting tumor treatment responses within the first few days of treatment. The monoclonal antibody, DAB4, or its chimeric derivative, chDAB4 (APOMAB ® ), targets the Lupus-associated or Sjögren Syndrome-B antigen (La/SSB). La/SSB is over-expressed in malignancy and is selectively targeted by chDAB4 in cancer cells dying after DNA-damaging treatment. Therefore, chDAB4 is a unique diagnostic tool that specifically detects dead cancer cells and could be used to distinguish between chemotherapy responsive and non-responsive patients. In this study, we performed preclinical validation studies using whole-body Positron-Emission Tomography (PET) to examine tumor and normal tissue uptake of 89 Zr-labeled chDAB4 in lung or ovarian tumor-bearing mice, which were left untreated or given cisplatin chemotherapy. Methods. The binding of chDAB4 and its conjugates to dead cisplatin-treated human lung and ovarian cancer cells was assessed in vitro as well as its Fc-dependent effector functions. Mice bearing xenografts of H460 lung cancer or A2780 ovarian cancer cells were untreated or given cisplatin chemotherapy followed 24 hours later by 89 Zr-labeled chDAB4. Post-cisplatin tumor responses were monitored using bioluminescence imaging and caliper measurements and 89 Zr-labeled chDAB4 tumor uptake was measured using an Albira SI PET imager and PMOD analysis software. On completion of experiments, organs were dissected and biodistribution of 89 Zr-labeled chDAB4 was measured using a Hidex gamma-counter. Results. The chDAB4 antibody bound only to dead A2780 and H460 cells, and its binding increased with cisplatin treatment in vitro . The chDAB4 antibody did not exhibit Fc-dependent effector functions. Chemotherapy significantly increased uptake of 89 Zr-labeled chDAB4 in tumors but not in normal tissues for each tumor model. The greatest differences in average uptake of 89 Zr-labeled chDAB4 in subcutaneous tumors were observed 3 days post-cisplatin chemotherapy compared to untreated mice, and before tumor shrinkage was evident. Conclusion. After administration of cisplatin chemotherapy, tumor xenograft uptake of 89 Zr-labeled chDAB4 was detected in vivo by PET imaging. Given that the chDAB4 mAb lacked effector activity and that malignant rather than normal tissues were targeted after chemotherapy, these results support clinical development of chDAB4 as both a predictive marker of chemotherapy response and a theranostic imaging agent, which may guide subsequent delivery of chDAB4-directed antibody drug or radio-conjugate anticancer therapies.
Publisher: American Society of Hematology
Date: 06-2008
Publisher: Research Square Platform LLC
Date: 31-07-2020
DOI: 10.21203/RS.3.RS-32059/V2
Abstract: Purpose. There are no currently approved non-invasive methods for detecting tumor treatment responses within the first few days of treatment. The monoclonal antibody, DAB4, or its chimeric derivative, chDAB4 (APOMAB ® ), targets the Lupus-associated or Sjögren Syndrome-B antigen (La/SSB). La/SSB is over-expressed in malignancy and is selectively targeted by chDAB4 in cancer cells that have died after DNA-damaging treatment. Therefore, chDAB4 could be used to distinguish between chemotherapy responsive and non-responsive patients. In this study, we performed preclinical validation studies using whole-body Positron-Emission Tomography (PET) to examine tumor and normal tissue uptake of 89 Zr-labeled chDAB4 in lung or ovarian tumor-bearing mice, which were left untreated or given cisplatin chemotherapy. Methods. The binding of chDAB4 and its conjugates to dead cisplatin-treated human lung and ovarian cancer cells was assessed in vitro as well as its Fc-dependent effector functions. Mice bearing xenografts of H460 lung cancer or A2780 ovarian cancer cells were untreated or given cisplatin chemotherapy followed 24 hours later by 89 Zr-labeled chDAB4. Post-cisplatin tumor responses were monitored using bioluminescence imaging and caliper measurements and 89 Zr-labeled chDAB4 tumor uptake was measured using an Albira SI PET imager and PMOD analysis software. On completion of experiments, organs were dissected and biodistribution of 89 Zr-labeled chDAB4 was measured using a Hidex gamma-counter. Results. The chDAB4 antibody bound only to dead A2780 and H460 cells, and its binding increased with cisplatin treatment in vitro . The chDAB4 antibody did not exhibit Fc-dependent effector functions. Chemotherapy significantly increased uptake of 89 Zr-labeled chDAB4 in tumors but not in normal tissues for each tumor model. The greatest differences in average uptake of 89 Zr-labeled chDAB4 in subcutaneous tumors were observed 3 days post-cisplatin chemotherapy compared to untreated mice, and before tumor shrinkage was evident. Conclusion. After administration of cisplatin chemotherapy, tumor xenograft uptake of 89 Zr-labeled chDAB4 was detected in vivo by PET imaging. Given that the chDAB4 mAb lacked effector activity and that malignant rather than normal tissues were targeted after chemotherapy, these results support clinical development of chDAB4 as both a predictive marker of chemotherapy response and a theranostic imaging agent, which may guide subsequent delivery of chDAB4-directed antibody drug or radio-conjugate anticancer therapies.
No related grants have been discovered for vasilios liapis.