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Objective Treatment options for non-hospitalised patients with coronavirus disease 2019 (COVID-19) to reduce morbidity, mortality and spread of the disease are an urgent global need. The over-the-counter histamine-2 receptor antagonist famotidine is a putative therapy for COVID-19. We quantitively assessed longitudinal changes in patient reported outcome measures in non-hospitalised patients with COVID-19 who self-administered high-dose famotidine orally. Design Patients were enrolled consecutively after signing written informed consent. Data on demographics, COVID-19 diagnosis, famotidine use, drug-related side effects, temperature measurements, oxygen saturations and symptom scores were obtained using questionnaires and telephone interviews. Based on a National Institute of Health (NIH)-endorsed Protocol to research Patient Experience of COVID-19, we collected longitudinal severity scores of five symptoms (cough, shortness of breath, fatigue, headaches and anosmia) and general unwellness on a four-point ordinal scale modelled on performance status scoring. All data are reported at the patient level. Longitudinal combined normalised symptom scores were statistically compared. Results Ten consecutive patients with COVID-19 who self-administered high-dose oral famotidine were identified. The most frequently used famotidine regimen was 80 mg three times daily (n=6) for a median of 11 days (range 5-21 days). Famotidine was well tolerated. All patients reported marked improvements of disease related symptoms after starting famotidine. The combined symptom score improved significantly within 24 hours of starting famotidine and peripheral oxygen saturation (n=2) and device recorded activity (n=1) increased. Conclusions The results of this case series suggest that high-dose oral famotidine is well tolerated and associated with improved patient-reported outcomes in non-hospitalised patients with COVID-19.Conventional antibody drug conjugates (ADC) utilize native surface-exposed lysines or cysteines on the antibody of interest to conjugate cytotoxic payload. The non-specific conjugation results in a mixture with variable drug-to-antibody ratios (DARs), conjugation sites, and ADCs that are often unstable in systemic circulation. ARX788 is an ADC consisting of a HER2-targeting antibody site-specifically conjugated with a potent anti-tubulin cytotoxic drug-linker, AS269. The site-specific conjugation is achieved by first incorporating the non-natural amino acid, para-acetyl phenylalanine (pAF), into the antibody, followed by covalent conjugation of AS269 to the pAF to form a highly stable oxime bond resulting in a DAR2 ADC. ARX788 exhibits significant, dose-dependent anti-tumor activity against HER2 expressing breast and gastric xenograft tumors. Pharmacokinetic (PK) studies in multiple species showed the highly stable nature of ARX788 with overlapping PK profiles for the intact ADC and total antibody. Metabolism studies demonstrated pAF-AS269 was the sole major metabolite of ARX788, with no evidence for the release of free drug often observed in conventional ADCs and responsible for adverse side effects. Furthermore, ARX788 demonstrated a favorable safety profile in monkeys with a Highest Non-Severely Toxic Dose (HNSTD) of 10 mg/kg, which was well above the efficacious dose level observed in preclinical tumor models, thus supporting clinical development of ARX788.Metastasis development is the leading cause of cancer-related mortality in pancreatic ductal adenocarcinoma (PDAC) and yet, few preclinical systems to recapitulate its full spreading process are available. selleck kinase inhibitor Thus, modeling of tumor progression to metastasis is urgently needed. In this work, we describe the generation of highly metastatic PDAC patient-derived xenograft (PDX) mouse models and subsequent single-cell RNA sequencing of circulating tumor cells (CTC), isolated by human HLA sorting, to identify altered signaling and metabolic pathways as well as potential therapeutic targets. The mouse models developed liver and lung metastasis with a high reproducibility rate. Isolated CTCs were highly tumorigenic, had metastatic potential and single-cell RNA sequencing showed that their expression profiles clustered separately from those of their matched primary and metastatic tumors and were characterized by low expression of cell cycle and extracellular matrix associated genes. CTC transcriptomics identified survivin (BIRC5), a key regulator of mitosis and apoptosis, as one of the highest upregulated genes during metastatic spread. Pharmacological inhibition of survivin with YM155 or survivin-knockdown promoted cell death in organoid models as well as anoikis, suggesting that survivin facilitates cancer cell survival in circulation. Treatment of metastatic PDX models with YM155 alone and in combination with chemotherapy hindered the metastatic development resulting in improved survival. Metastatic PDX mouse model development allowed the identification of survivin as a promising therapeutic target to prevent the metastatic dissemination in PDAC.The Phosphatidylinositol 3 kinase (PI3K) pathway is considered a master regulator for cancer due to its frequent activation, making it an attractive target for pharmacologic intervention. While substantial efforts have been made to develop drugs targeting PI3K signaling, few drugs have been able to achieve the inhibition necessary for effective tumor control at tolerated doses. HSP90 is a chaperone protein that is overexpressed and activated in many tumors and as a consequence, small molecule ligands of HSP90 are preferentially retained in tumors up to 20 times longer than in normal tissue. We hypothesize that the generation of conjugates that use a HSP90 targeting ligand and a payload such as Copanlisib, may open the narrow therapeutic window of this and other PI3K inhibitors. In support of this hypothesis, we have generated a HSP90-PI3K drug conjugate, T-2143 and utilizing xenograft models, demonstrate rapid and sustained tumor accumulation of the conjugate, deep pathway inhibition, and superior efficacy than the PI3K inhibitor on its own. Selective delivery of T-2143 and the masking of the inhibitor active site was also able to mitigate a potentially dose limiting side effect of Copanlisib, hyperglycemia. These data demonstrate that by leveraging the preferential accumulation of HSP90 targeting ligands in tumors, we can selectively deliver a PI3K inhibitor leading to efficacy in multiple tumor models without hyperglycemia in mice. These data highlight a novel drug delivery strategy that allows for the potential opening of a narrow therapeutic window through specific tumor delivery of anticancer payloads and reduction of toxicity.