Antibody-drug conjugates (ADCs) convey highly potent anticancer drugs to antigen-expressing tumor cells, thereby sparing healthy tissues throughout the body. Pharmacokinetics and tolerability of ADCs ...are predominantly influenced by the drug-antibody ratio (DAR) of the conjugates, which is to-date limited to a value of 3-4 drugs per antibody in ADCs under clinical investigations. Here, we report the synthesis of monodisperse (
discrete) polysarcosine compounds and their use as a hydrophobicity masking entity for the construction of highly-loaded homogeneous β-glucuronidase-responsive antibody-drug conjugates (ADCs). The highly hydrophilic drug-linker platform described herein improves drug-loading, physicochemical properties, pharmacokinetics and
antitumor efficacy of the resulting conjugates.
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IJS, KILJ, NUK, UL, UM, UPUK
Acute exercise induces transient modifications in the tumor microenvironment and has been linked to reduced tumor growth along with increased infiltration of immune cells within the tumor in mouse ...models. In this study, we aimed to evaluate the impact of acute exercise before treatment administration on tumor growth in a mice model of MC38 colorectal cancer receiving an immune checkpoint inhibitor (ICI) and chemotherapy. Six-week-old mice injected with colorectal cancer cells (MC38) were randomized in 4 groups: control (CTRL), immuno-chemotherapy (TRT), exercise (EXE) and combined intervention (TRT/EXE). Both TRT and TRT-EXE received ICI: anti-PD1-1 (1 injection/week) and capecitabine + oxaliplatin (5 times a week) for 1 week (experimentation 1), 3 weeks (experimentation 2). TRT-EXE and EXE groups were submitted to 50 minutes of treadmill exercise before each treatment administration. Over the protocol duration, tumor size has been monitored daily. Tumor growth and microenvironment parameters were measured after the intervention on Day 7 (D7) and Day 16 (D16). From day 4 to day 7, tumor volumes decreased in the EXE/TRT group while remaining stable in the TRT group (p=0.0213). From day 7 until day 16 tumor volume decreased with no significant difference between TRT and TRT/EXE. At D7 the TRT/EXE group exhibited a higher total infiltrate T cell (p=0.0118) and CD8+ cytotoxic T cell (p=0.0031). At D16, tumor marker of apoptosis, vascular integrity and inflammation were not significantly different between TRT and TRT/EXE. Our main result was that acute exercise before immuno-chemotherapy administration significantly decreased early-phase tumor growth (D0 to D4). Additionally, exercise led to immune cell infiltration changes during the first week after exercise, while no significant molecular alterations in the tumor were observed 3 weeks after exercise.
Bacterial lipopolysaccharides (LPS) are potent innate immunostimulants targeting the Toll-like receptor 4 (TLR4), an attractive and validated target for immunostimulation in cancer therapy. Although ...LPS possess anti-tumor activity, toxicity issues prevent their systemic administration at effective doses in humans. We first demonstrated that LPS formulated in liposomes preserved a potent antitumor activity
upon systemic administration in syngeneic models, and significantly enhance the antitumor activity of the anti-CD20 antibody rituximab in mice xenografted with the human RL lymphoma model. Liposomal encapsulation also allowed a 2-fold reduction in the induction of pro-inflammatory cytokines by LPS. Mice receiving an intravenous administration demonstrated a significant increase of neutrophils, monocytes and macrophages at the tumor site as well as an increase of macrophages in spleen. Further, we chemically detoxified LPS to obtain MP-LPS that was associated with a 200-fold decrease in the induction of proinflammatory cytokines. When encapsulated in a clinically approved liposomal formulation, toxicity, notably pyrogenicity (10-fold), was limited while the antitumor activity and immunoadjuvant effect were maintained. This improved tolerance profile of liposomal MP-LPS was associated with the preferential activation of the TLR4-TRIF pathway. Finally,
studies demonstrated that stimulation with encapsulated MP-LPS reversed the polarization of M2 macrophages towards an M1 phenotype, and a phase 1 trial in healthy dogs validated its tolerance upon systemic administration up to very high doses (10µg/kg). Altogether, our results demonstrate the strong therapeutic potential of MPLPS formulated in liposomes as a systemically active anticancer agent, supporting its evaluation in patients with cancer.
The development of targeted therapies has drastically improved the outcome of patients with different types of cancer. T‐DM1 (trastuzumab‐emtansine) is an antibody‐drug conjugate used for the ...treatment of HER2‐positive breast cancer combining the FDA approved mAb (monoclonal antibody) trastuzumab and the microtubule cytotoxic agent DM1 (emtansine). Despite clinical successes achieved by targeted therapies, a large number of patients develop resistance during treatment. To explore mechanisms of resistance to T‐DM1, the MDA‐MB‐361 HER2‐positive breast cancer cell line was exposed in vitro to T‐DM1 in the absence or presence of ciclosporin A. Previously reported mechanisms of resistance such as trastuzumab‐binding alterations, MDR1 upregulation, and SLC46A3 downregulation were not observed in these models. Despite a decrease in HER2 expression at the cell surface, both resistant cell lines remained sensitive to HER2 targeted therapies such as mAbs and tyrosine kinase inhibitors. In addition, sensitivity to DNA damaging agents and topoisomerase inhibitors were unchanged. Conversely resistance to anti‐tubulin agents increased. Resistant cells displayed a decreased content of polymerized tubulin and a decreased content of βIII tubulin although the downregulation of βIII tubulin by siRNA in the parental cell line did not modified the sensitivity to T‐DM1. Both cell lines resistant to T‐DM1 also presented giant aneuploid cells. Several SLC (solute carrier) transporters were found to be differentially expressed in the resistant cells in comparison to parental cells. These results suggest that some characteristics such as increased baseline aneuploidy and altered intracellular drug trafficking might be involved in resistance to T‐DM1.
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FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
Antibody-drug conjugates (ADCs) convey highly potent anticancer drugs to antigen-expressing tumor cells, thereby sparing healthy tissues throughout the body. Pharmacokinetics and tolerability of ADCs ...are predominantly influenced by the drug-antibody ratio (DAR) of the conjugates, which is to-date limited to a value of 3-4 drugs per antibody in ADCs under clinical investigations. Here, we report the synthesis of monodisperse (
i.e.
discrete) polysarcosine compounds and their use as a hydrophobicity masking entity for the construction of highly-loaded homogeneous β-glucuronidase-responsive antibody-drug conjugates (ADCs). The highly hydrophilic drug-linker platform described herein improves drug-loading, physicochemical properties, pharmacokinetics and
in vivo
antitumor efficacy of the resulting conjugates.
A new antibody-drug conjugate (ADC) chemical drug-linker platform based on polysarcosine enables increased drug-loading, improved pharmacokinetics and exquisite
in vivo
potency.
Full text
Available for:
IJS, KILJ, NUK, UL, UM, UPUK
A new antibody-drug conjugate (ADC) chemical drug-linker platform based on polysarcosine enables increased drug-loading, improved pharmacokinetics and exquisite
in vivo
potency.
Antibody-drug ...conjugates (ADCs) convey highly potent anticancer drugs to antigen-expressing tumor cells, thereby sparing healthy tissues throughout the body. Pharmacokinetics and tolerability of ADCs are predominantly influenced by the drug-antibody ratio (DAR) of the conjugates, which is to-date limited to a value of 3–4 drugs per antibody in ADCs under clinical investigations. Here, we report the synthesis of monodisperse (
i.e.
discrete) polysarcosine compounds and their use as a hydrophobicity masking entity for the construction of highly-loaded homogeneous β-glucuronidase-responsive antibody-drug conjugates (ADCs). The highly hydrophilic drug-linker platform described herein improves drug-loading, physicochemical properties, pharmacokinetics and
in vivo
antitumor efficacy of the resulting conjugates.
Full text
Available for:
IJS, KILJ, NUK, UL, UM, UPUK
Abstract
Adipose tissue is often reduced to its role in fat storage and metabolic support for tumor cells. However, several studies have shown an adipocyte-mediated resistance effect to various ...anticancer therapies. However, the responsible agent(s), the mechanism(s) and the signaling pathway(s) involved in this resistance remain unclear. In the present study, we assessed the cytotoxic effect of lapatinib on several breast cancer cell lines in the presence or absence of adipocyte-conditioned medium. We performed different physical and chemical treatments on these conditioned media in order to separate and identify the different molecules and agents involved. In parallel, we investigated the changes that occurs in breast tumor cells following the contact with adipocyte-conditioned medium and the exposure to lapatinib both at transcriptional and protein level. In order to validate our hypothesis in vivo, we created a mouse model reproducing the contact between adipose tissue and tumors. Our results showed that tumor cells exposed to adipocyte-conditioned medium were less sensitive to lapatinib-mediated cytotoxic effects and cell cycle blockade than cells grown in standard culture medium. For example, we found that the IC50 was approximately seven-fold increased with lapatinib for tumor cells exposed to adipocyte-conditioned medium compared to the cells kept in control medium. This resistance was observed with the conditioned medium obtained both from human and murine adipocytes and confirmed on different breast tumor cell lines overexpressing HER2. Using a xenograft of normal human adipose tissue with implantation of tumor cells in contact to this adipose tissue, we also confirmed the protective effect against the antitumoral activity of lapatinib in vivo. The nature of the responsible agents of the resistance has been partly elucidated as well as the mechanisms. Indeed, it seems that the presence of soluble factors released from adipocytes such as lipolysis and metabolism products are required to limit the effect of lapatinib on tumor cells. The exposure of tumor cells to adipocyte-conditioned medium triggered changes on the lapatinib-mediated cell cycle blockade and on the expression of cell cycle regulation dependent proteins such as AKT, P27 and cyclins. In conclusion, compounds released from adipocytes reduced the lapatinib induced cytotoxicity on breast cancer cells overexpressing HER2 by interfering with the AKT signaling pathway. These results suggest possible strategies to counteract tumor cell resistance to lapatinib, by targeting adipocyte-released mediators.
Citation Format: Aline Geneste, Minh Ngoc Duong, Aurore Cleret, Sabine Beaumel, Kamel Chettab, Emmanuel Delay, Philippe Valet, Lars Petter Jordheim, Charles Dumontet. Adipocyte-released agents induce resistance of breast cancer cells to lapatinib abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5835.
Abstract
Clinical success of Trastuzumab-emtansine (T-DM1, Kadcyla) lead its extended approval as a post-surgical adjuvant treatment in early stage HER-2-positive breast cancer. However, intrinsic ...and acquired resistance remains a major limitation to its clinical efficacy. Adipocytes were shown to exhibit a pro-survival cross talk with breast cancer cells, limiting their sensitivity to T-DM1 and raising the question of metabolic alterations involved in this resistance phenotype. To explore the role of tumor cell metabolic plasticity in T-DM1 resistance, xenografts of the human HER-2 positive breast cancer model BT-474 were exposed in vivo to increasing doses of T-DM1. BT-474 WT and R tumors were characterized by RNAseq and primary explants of in vivo tumors were cultured and analyzed in vitro. Although HER-2 levels were found to be strongly reduced in resistant cells, no increase of its pro-survival downstream partners were observed at the transcriptomic level. Conversely, PIK3CA and KRAS were respectively 2.5- and 2-times downregulated in BT-474 R according to RNAseq data, suggesting the implementation of compensatory pathways for cell survival and proliferation. Tumors resistant to T-DM1 exhibited alterations in lipid metabolism, including an increase in lipid droplet content observed by ORO staining, upregulation of fatty acid metabolism pathways, and lipid transporter FABP4 overexpression. Cells resistant to T-DM1 survived to 2-deoxyglucose treatment (100 mM) as well as glucose deprivation in vitro while these conditions were cytotoxic to BT-474 WT cells. In addition, BT-474 R cells were resistant to palmitate exposure, suggesting energy production is monitored by an increased lipid import and metabolism. Ferroptotic cell death and associated lipid peroxidation have recently been associated with alterations in lipid metabolism. H2D-CFDA staining revealed a 2-fold increase in ROS content in R cells at the basal state compared to WT cells. In vitro, BT-474 R cells were highly sensitive to ROS inducers such as H2O2 and bleomycin when compared to WT cells (IC50s were 7- and 30-fold higher in WT compared to R cells for H202 and bleomycin, respectively). This unusually strong cytotoxicity of H2O2 was found to be correlated with a significant increase of ROS content within the resistant cells compared to wild type cells after H2O2 treatment. Additionally, inhibitors of ferroptosis such as GPX4, and the antiporter system xct were found to be downregulated in resistant cells, while the GPX4 inhibitor RSL3 was 5-fold more cytotoxic in cells resistant to T-DM1 than in WT cells. T-DM1 -resistant cells thus demonstrate increased fatty acid uptake, decreased ability to eliminate ROS and enhanced sensitivity to ferroptosis inducers. Altogether, these results suggest that ferroptosis could constitute a promising target for T-DM1-resistant tumors.
Citation Format: Louise Conilh, Juliette Sauveur, Sabine Beaumel, Claire Scheffges, Estelle Nunez, David Cheillan, Charles Dumontet. Inability to regulate ROS content confers sensitivity to ferroptosis in breast cancer cells resistant to T-DM1 abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1779.
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