Selenosemicarbazone Metal Complexes as Potential Metal-based Drugs

The discovery of the anticancer activity of cisplatin has marked the emergence of modern Inorganic Medicinal Chemistry. This field of research is concerned with the application of inorganic compounds to therapy or diagnosis of disease. In particular, metal coordination of bioactive ligands has gained recognition in drug design. The interaction between transition metal ions and the organic drugs could enhance their diagnostic and therapeutic potentials by improving the stability and/or bioavailability or by achieving a metal-drug synergism through a dual or multiple mechanism of action. The isosteric replacement of sulfur by selenium in thiosemicarbazones leads to selenosemicarbazones. This class of compounds exhibit numerous biological activities like antitumor, antimicrobial, antiviral etc. and, in most cases, they were more pronounced in comparison to the sulfur analogues. On the other hand, while the effect of transition metal complexation on the biological activity of thiosemicarbazones has been widely studied, the pharmacological activity of the corresponding metal-selenosemicarbazone compounds has been less explored. In this work, the most relevant results related to the selenosemicarbazone metal complexes as potential metal-based drugs have been reviewed.

Regorafenib enhances anti-PD1 immunotherapy efficacy in murine colorectal cancers and their combination prevents tumor regrowth

Background Patients with advanced colorectal cancer (CRC) have a poor prognosis. Combinations of immunotherapies and anti-angiogenic agents are currently being evaluated in clinical trials. In this study, the multikinase inhibitor regorafenib (REG) was combined with an anti-programmed cell death protein 1 (aPD1) antibody in syngeneic murine microsatellite-stable (MSS) CT26 and hypermutated MC38 colon cancer models to gain mechanistic insights into potential drug synergism. Methods Growth and progression of orthotopic CT26 and subcutaneous MC38 colon cancers were studied under treatment with varying doses of REG and aPD1 alone or in combination. Sustained effects were studied after treatment discontinuation. Changes in the tumor microenvironment were assessed by dynamic contrast-enhanced MRI, and histological and molecular analyses. Results In both models, REG and aPD1 combination therapy significantly improved anti-tumor activity compared with single agents. However, in the CT26 model, the additive benefit of aPD1 only became apparent after treatment cessation. The combination treatment efficiently prevented tumor regrowth and completely suppressed liver metastasis, whereas the anti-tumorigenic effects of REG alone were abrogated soon after drug discontinuation. During treatment, REG significantly reduced the infiltration of immunosuppressive macrophages and regulatory T (Treg) cells into the tumor microenvironment. aPD1 significantly enhanced intratumoral IFNγ levels. The drugs synergized to induce sustained M1 polarization and durable reduction of Treg cells, which can explain the sustained tumor suppression. Conclusions This study highlights the synergistic immunomodulatory effects of REG and aPD1 combination therapy in mediating a sustained inhibition of colon cancer regrowth, strongly warranting clinical evaluation in CRC, including MSS tumors.

A landscape of synergistic drug combinations in non-small-cell lung cancer

Targeted therapeutics have advanced cancer treatment, but single agent activity remains limited by de novo and acquired resistance. Combining targeted drugs is broadly seen as a way to improve treatment outcome, motivating the ongoing search for efficacious combinations. To identify synergistic targeted therapy combinations and study the impact of tumor heterogeneity on combination outcome, we systematically tested over 5,000 two drug combinations at multiple doses across a collection of 81 non-small cancer cell lines. Both known and novel synergistic combinations were identified. Strikingly, very few combinations yield synergy across the majority of cell line models. Importantly, synergism mainly arises due to sensitization of single agent resistant models, rather than further sensitize already sensitive cell lines, frequently via dual targeting of a single or two highly interconnected pathways. This drug combinations resource, the largest of its kind should help delineate new synergistic regimens by facilitating the understanding of drug synergism in cancer.

Phase 1A clinical trial of the first-in-class fascin inhibitor NP-G2-044 evaluating safety and anti-tumor activity in patients with advanced and metastatic solid tumors.

2548 Background: Fascin inhibitors block tumor metastasis and increase antigen uptake in intra-tumoral dendritic cells. Filopodia, finger-like protrusions on cell surfaces, are necessary for migration of metastatic tumor cells and intra-tumoral dendritic cells. Fascin is the primary actin cross-linker in filopodia and elevated levels correlate with increased risk of metastasis, disease progression and mortality. NP-G2-044 is a novel small molecule that inhibits function of fascin. Pre-clinical data demonstrate drug-associated reductions in tumor growth and metastasis, enhanced immune response and survival in treated animals, and drug-drug synergism when combined with anti-PD-1 antibodies. Methods: This multicenter phase 1A clinical trial was designed to evaluate safety and tolerability of NP-G2-044 and to identify the drug’s recommended phase 2 dose (RP2D) using a 3+3 dose escalation design. NP-G2-044 was administered to patients (pts.) with treatment-refractory solid tumor malignancies as a single oral daily dose for 6-week cycles that included 4 weeks on (daily dosing) and 2 weeks off (rest). Results: A total of 23 pts. were enrolled in 7 dose cohorts ranging from 200-2100 mg. QD. Overall, NP-G2-044 appeared well-absorbed and distributed with Tmax of ̃4 hrs and T1/2 of 20-24 hrs. Across all cohorts, no DLTs, drug-related SAEs or patient deaths were observed. Based on PK and safety findings, 1600 mg. daily was selected as the provisional RP2D. While no formal RECIST-based objective responses were observed, consistent with the drug’s non-cytotoxic mechanism of action, preliminary signals of anti-tumor and anti-metastatic activity were observed. These include dose proportional increases in duration of treatment, progression-free-survival, and metastasis-free interval, in particular for 4/4 late-stage ovarian cancer patients (table). Comparison of time on treatment (TOT) for ovarian cancer patients. Conclusions: In this first-in-human clinical trial, the novel fascin inhibitor, NP-G2-044, appeared safe and well tolerated. Signals of single-drug anti-tumor and anti-metastatic activity were observed. A phase 2A clinical trial with a particular focus on Ovarian Cancer will seek to elucidate signals of RP2D activity in both monotherapy and the combination of NP-G2-044 with anti-PD-(L)1 immune checkpoint inhibitors. Clinical trial information: NCT03199586. [Table: see text]

SYNERGxDB: an integrative pharmacogenomic portal to identify synergistic drug combinations for precision oncology

Drug-combination data portals have recently been introduced to mine huge amounts of pharmacological data with the aim of improving current chemotherapy strategies. However, these portals have only been investigated for isolated datasets, and molecular profiles of cancer cell lines are lacking. Here we developed a cloud-based pharmacogenomics portal called SYNERGxDB (http://SYNERGxDB.ca/) that integrates multiple high-throughput drug-combination studies with molecular and pharmacological profiles of a large panel of cancer cell lines. This portal enables the identification of synergistic drug combinations through harmonization and unified computational analysis. We integrated nine of the largest drug combination datasets from both academic groups and pharmaceutical companies, resulting in 22 507 unique drug combinations (1977 unique compounds) screened against 151 cancer cell lines. This data compendium includes metabolomics, gene expression, copy number and mutation profiles of the cancer cell lines. In addition, SYNERGxDB provides analytical tools to discover effective therapeutic combinations and predictive biomarkers across cancer, including specific types. Combining molecular and pharmacological profiles, we systematically explored the large space of univariate predictors of drug synergism. SYNERGxDB constitutes a comprehensive resource that opens new avenues of research for exploring the mechanism of action for drug synergy with the potential of identifying new treatment strategies for cancer patients.

Survival and prognostic tests in a real-world phase II experience with a safe, moderate-dose, sequential chemotherapy (CT) algorithm (ALGO) for metastatic pancreatic adenocarcinoma (PANC).

e16763 Background: Gemcitabine (G), 5-fluorouracil (F), leucovorin (L), irinotecan (I), and oxaliplatin (O), (GFLIO) is safe, employs moderate 1/2-1/3 dosages, offers expanded eligibility (0-2 ECOG PS; no age limit)). Each step reverse resistance (RR) to CT; drug synergism 4-6 simultaneous pairs) improve responses (Rs) and survival (S) (Bruckner ASCO 05, 08, 11, AntiCancer Res 2016; 36 (1), 2018; 38 (1) (ACR), and the immune system (Correale P: J. Immunother 2014; 37). M Caraglia: Front Oncol. 2019). Methods: Eligibility: intent to treat active metastatic PANC, no prior CT: any age: PS 0-2 and expected > 6 weeks S. IRB required safety < 1/10 severe events. ALGO in mg/m2: G 500, F 12-1500 over 24 hrs, L 180, I 80, day2 O (GFLIO) q2 wks, and on progression added in sequence, day 2, docetaxel 20-25 and good counts only mitomycin C 3-6 then bevacizumab 10mg/kg with prior monitoring and modifications (ACR). Median 12, 18, 24 mos Overall Survival (OS), Kaplan Meier estimates with 95% CI were evaluated with age, sex and normal nl and abnl baseline bloods: neutrophils N ANC; Lymphs Ly ALC; platelets; albumin (ALB); Alkaline phosphatase (Alk Ph) abn N alb 3.5 N/L; 2.1 L/monocyte ratios and the A.L.A.N (AS) composite prognostic score (M. Salati E.J.Ca. 2019; 117: 84-90). Results: OS @ 6, 12, 18 & 24 mos, for 53 pts, was 75; 57; 36; 26 % (+/- 8-10%). Median M S was 14.5 mo (CI 9-17mos); S @ all ages ≥ 60, 65 or 70, was not inferior. Women's M S 17 mo. was > men's 10.5: 95/65; 75/46; 48/29; 42/29%. AS for abnl tests was: 0 (18pts): 93: 81: 48; 34% & MS 17 mo vs 1-2 (23)90: 58;42;32% & MS 15.5mo vs 3-4 (12)MS 3 mo. Pts with best 17-14.5 mo MS had nl AS 0 > Alb > AS 1-2 > APh > ANC. Pts with worst 3-6 mo MS had abnl: AS 3-4 < Alb < ANC. No pt had severe infection, neuropathy or gastroenteritis. Pts -/+ 75-100gm ascorbic acid, 25, did not have inferior S in ALAN subsets (H.Bruckner AACR 17). Conclusions: The sequential moderate dose CT ALGO improves eligbility and provides pts with metastatic PANC of any age a well tolerated CT regimen with a high therapeutic index and strong, 12, 18, 24 mo, survival. Prognostic tests can identify subgroups ≥ 75% with favorable vs. unfavorable criteria and improve personalized choices and measures to remedy individual risk factors. Clinical trial information: NCT01905150 .