Biology subjects

Kossatz, S.

Publications and source records attributed to Kossatz, S..

6 recordsLinked to original sources

bioRxiv2026

High Drug-Loading Rucaparib-FdUMP Nanocarriers for Colorectal Cancer Combination Therapy

Combination chemotherapy remains the standard of care for advanced colorectal cancer, yet the clinical benefit is limited by off-target toxicity and insufficient tumor drug exposure. Co-administration of 5-fluorouracil (5-FU) with poly(ADP-ribose) polymerase (PARP) inhibitors such as rucaparib (RUC) can potentiate 5-FU-induced DNA damage by suppressing DNA repair but achieving robust co-delivery at defined ratios and high payload remains challenging. Here, we report high drug-loading core@shell nanocarriers (RUC@[ZrO][FdUMP]) that co-deliver RUC and the active 5-FU metabolite fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP). Nanocarriers were synthesized via a solvent-antisolvent approach to form a tocopherol phosphate (TocP)-stabilized RUC core followed by the growth of an amorphous [ZrO][FdUMP] shell, yielding an overall drug load of 59 wt%. Dual fluorescence (shell incorporation of DUT647 and intrinsic RUC emission) enabled quantitative tracking and revealed rapid uptake in HCT116 and HT29 colorectal cancer cells and tumor accumulation in a subcutaneous HT29 xenograft. In vitro, RUC@[ZrO][FdUMP] showed cytotoxicity comparable to the free-drug combination, induced S-phase arrest, and increased {gamma}H2AX foci, consistent with replication stress and DNA double-strand break formation. Drug-drug interaction analysis demonstrated synergistic activity of the RUC/FdUMP pair in colorectal cancer cells. Together, these results establish RUC@[ZrO][FdUMP] as a high-payload nanocarrier platform for co-delivering synergistic PARP inhibitor/fluoropyrimidine combinations, supporting further development and in vivo evaluation of this co-delivery strategy for colorectal cancer therapy. TOC Graphics O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=50 SRC="FIGDIR/small/727099v1_ufig1.gif" ALT="Figure 1"> View larger version (15K): org.highwire.dtl.DTLVardef@dd9ad6org.highwire.dtl.DTLVardef@e07aecorg.highwire.dtl.DTLVardef@1a63505org.highwire.dtl.DTLVardef@e30d58_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

Synthesis and Preclinical Development of a Novel 68Ga/89Zr-Labelled α{nu}β6-Integrin Targeting Trimer

The v{beta}6 integrin has emerged as a valuable target for theranostic applications in nuclear medicine with high applicability across a variety of cancers, including head-and-neck, lung, breast, and pancreatic carcinomas. [Ga]Ga-Trivehexin is a prominent example of a diagnostic tracer targeting this integrin. In this work, we aimed to expand on this concept by developing FSC(PEG4-v{beta}6), a novel tracer that retains the Trivehexin design, but features PEGylated spacers and replaces the TRAP chelator with Fusarinine C (FSC), enabling labelling with Zirconium-89 in addition to Gallium-68. Preclinical characterization of [Ga]Ga/[Zr]Zr-FSC(PEG4-v{beta}6) included affinity determination towards the v{beta}6 integrin and cellular uptake studies in v{beta}6-positive H2009 cells. A subcutaneously xenografted H2009 tumor model was used to assess the PET imaging potential and biodistribution at early time points with the Gallium-68-labelled compound, and at later time points (up to 6 days post-injection) with the Zirconium-89-labelled version. While [Ga]Ga-FSC(PEG4-v{beta}6) exhibited moderate binding to v{beta}6, its affinity, cellular internalization, and tumor uptake in vivo were lower compared to [Ga]Ga-Trivehexin. Notably, this decreased target engagement was associated with reduced nonspecific binding, which we primarily attributed to the incorporation of PEGylated linkers. Despite indication of in vivo degradation of [Zr]Zr-FSC(PEG4-v{beta}6), still a meaningful evaluation of pharmacokinetics and biodistribution at extended time points was feasible, indicating its suitability for prolonged imaging studies.

cancer biology↗

bioRxiv2024

Limitations of the radiotheranostic concept in neuroendocrine tumors due to lineage-dependent somatostatin receptor expression on hematopoietic stem and progenitor cells

Radiopharmaceutical therapy (RPT) has become an effective treatment option for neuroendocrine tumors (NETs) and castration-resistant prostate cancer and is in clinical development for a growing number of indications. One of the major advantages of theranostic RPT is that the distribution of radiopharmaceuticals in the human body can be imaged, and radiation doses to the patients organs can be calculated. However, accurate dosimetry may be fundamentally limited by microscopic heterogeneity of radiopharmaceutical distribution. We developed fluorescent analogs of somatostatin-receptor-subtype 2 (SSTR2) targeting Lutetium-177 labelled radiopharmaceuticals that are clinically used in patients with neuroendocrine tumors (NETs) and studied their uptake by hematopoietic stem and progenitor cells (HSPC). Hematopoietic stem cells (HSCs) and multipotent progenitor cells (MPPs) showed high and specific SSTR2-ligand uptake, which was at similar levels as neuroendocrine tumor cells. Furthermore, they displayed a several-fold higher uptake of SSTR2-antagonists than of SSTR2-agonists. HSPC treatment with a 177Lu-labelled antagonist and agonist showed a stronger reduction of HSC proliferation by the antagonist. Due to the scarcity of HSCs and MPPs, their contribution to total bone marrow uptake of SSTR2-ligands is not detectable in imaging-based dosimetry studies. This likely explains why SSTR2-antagonists caused pancytopenia in clinical trials despite safe dosimetry estimates. In conclusion, target expression heterogeneity can lead to underestimation of radiopharmaceutical toxicity and should be considered when designing clinical trials for new radiopharmaceuticals. The implications of our findings go beyond somatostatin receptor-targeted radiopharmaceuticals and suggest more generally that first-in-human studies should not only be guided by radiation dosimetry from imaging studies but should also include careful escalation of the administered therapeutic activity. The MMC technology is modular and can be applied to other peptide or protein-based radiopharmaceuticals to study cellular distribution and potential bone marrow uptake prior to clinical testing.

cancer biology↗

bioRxiv2021

Combined SHP2 and ERK inhibition for the treatment of KRAS-driven Pancreatic Ductal Adenocarcinoma

Mutant KRAS is present in over 90% of pancreatic as well as 30-40% of lung and colorectal cancers and is one of the most common oncogenic drivers. Despite decades of research and the recent emergence of isoform-specific KRASG12C-inhibitors, most mutant KRAS isoforms, including the ones frequently associated with pancreatic ductal adenocarcinoma (PDAC), cannot be targeted directly. Moreover, targeting single RAS downstream effectors induces adaptive mechanisms leading to tumor recurrence or resistance. We report here on the combined inhibition of SHP2, a non-receptor tyrosine phosphatase upstream of KRAS, and ERK, a serine/threonine kinase and a key molecule downstream of KRAS in PDAC. This combination shows synergistic anticancer activity in vitro, superior disruption of the MAPK pathway, and significantly increased apoptosis induction compared to single-agent treatments. In vivo, we demonstrate good tolerability and efficacy of the combination. Concurrent inhibition of SHP2 and ERK induces significant tumor regression in multiple PDAC mouse models. Finally, we show evidence that 18F-FDG PET scans can be used to detect and predict early drug responses in animal models. Based on these compelling results, we will investigate this drug combination in a clinical trial (SHERPA, SHP2 and ERK inhibition in pancreatic cancer, NCT04916236), enrolling patients with KRAS-mutant PDAC.

cancer biology↗

bioRxiv2019

PARP1 as a biomarker for early detection and intraoperative tumor delineation in epithelial cancers - first-in-human results

Major determining factors for survival of patients with oral, oropharyngeal, and esophageal cancer are early detection, the quality of surgical margins, and the contemporaneous detection of residual tumor. Intuitively, the exposed location at the epithelial surface qualifies these tumor types for utilization of visual aids to assist in discriminating tumor from healthy surrounding tissue. Here, we explored the DNA repair enzyme PARP1 as imaging biomarker and conducted optical imaging in animal models, human tissues and as part of a first-in-human clinical trial. Our data suggests that PARP1 is a quantitative biomarker for oral, oropharyngeal, and esophageal cancer and can be visualized with PARPi-FL, a fluorescently labeled small molecule contrast agent for topical or intravenous delivery. We show feasibility of PARPi-FL-assisted tumor detection in esophageal cancer, oropharyngeal and oral cancer. We developed a contemporaneous PARPi-FL topical staining protocol for human biospecimens. Using fresh oral cancer tissues within 25 min of biopsy, tumor and margin samples were correctly identified with >95% sensitivity and specificity without terminal processing. PARPi-FL imaging can be integrated into clinical workflows, potentially providing instantaneous assessment of the presence or absence of microscopic disease at the surgical margin. Additionally, we showed first-in-human PARPi-FL imaging in oral cancer. In aggregate, our preclinical and clinical studies have the unifying goal of verifying the clinical value of PARPi-FL-based optical imaging for early detection and intraoperative margin assignment.

clinical trials↗

bioRxiv2019

Targeted brain tumor radiotherapy using an Auger emitter

Glioblastoma multiforme is a highly aggressive form of brain cancer whose location, tendency to infiltrate healthy surrounding tissue, and heterogeneity significantly limit survival, with scant progress having been made in recent decades. 123I-MAPi (Iodine-123 Meitner-Auger PARP1 inhibitor) is a precise therapeutic tool composed of a PARP1 inhibitor radiolabeled with an Auger- and gamma-emitting iodine isotope. Here, the PARP inhibitor, which binds to the DNA repair enzyme PARP1, specifically targets cancer cells, sparing healthy tissue, and carries a radioactive payload within reach of the cancer cells DNA. The high relative biological efficacy of Auger electrons within their short range of action is leveraged to inflict DNA damage and cell death with high precision. The gamma ray emission of 123I-MAPi allows for the imaging of tumor progression and therapy response, and for patient dosimetry calculation. Here we demonstrated the efficacy and specificity of this small molecule radiotheranostic in a complex preclinical model. In vitro and in vivo studies demonstrate high tumor uptake and a prolonged survival in mice treated with 123I-MAPi when compared to vehicle controls. Different methods of drug delivery were investigated to develop this technology for clinical applications, including convection enhanced delivery (CED) and intrathecal injection. Taken together, these results represent the first full characterization of an Auger-emitting PARP inhibitor, demonstrate a survival benefit in mouse models of GBM, and confirm the high potential of 123I-MAPi for clinical translation.\n\nOne Sentence SummaryA novel PARP1-targeted Auger radiotherapeutic shows translational potential as a theranostic tool for imaging and killing cancer cells, resulting in tumor delineation and prolonged survival in a glioblastoma model.

cancer biology↗