Discovery of tetrazolo-pyridazine-based small molecules as inhibitors of MACC1-driven cancer metastasis

Metastasis is directly linked to poor prognosis of cancer patients and warrants search for effective anti-metastatic drugs. MACC1 is a causal key molecule for metastasis. High MACC1 expression is prognostic for metastasis and poor survival. Here, we developed novel small molecule inhibitors targeting MACC1 expression to impede metastasis formation. We performed a human MACC1 promoter-driven luciferase reporter-based high-throughput screen (HTS; 118.500 compound library) to identify MACC1 transcriptional inhibitors. HTS revealed 1,2,3,4-tetrazolo[1,5-b]pyridazine-based compounds as efficient transcriptional inhibitors of MACC1 expression, able to decrease MACC1-induced cancer cell motility in vitro. Structure-activity relationships identified the essential inhibitory core structure. Best candidates were evaluated for metastasis inhibition in xenografted mouse models demonstrating metastasis restriction. ADMET showed high drug-likeness of these new candidates for cancer therapy. The NFκB pathway was identified as one mode of action targeted by these compounds. Taken together, 1,2,3,4-tetrazolo[1,5-b]pyridazine-based compounds are effective MACC1 inhibitors and pose promising candidates for anti-metastatic therapies particularly for patients with MACC1-overexpressing cancers, that are at high risk to develop metastases. Although further preclinical and clinical development is necessary, these compounds represent important building blocks for an individualized anti-metastatic therapy for solid cancers

Drug-perturbation-based stratification of blood cancer

As new generations of targeted therapies emerge and tumor genome sequencing discovers increasingly comprehensive mutation repertoires, the functional relationships of mutations to tumor phenotypes remain largely unknown. Here, we measured ex vivo sensitivity of 246 blood cancers to 63 drugs alongside genome, transcriptome, and DNA methylome analysis to understand determinants of drug response. We assembled a primary blood cancer cell encyclopedia data set that revealed disease-specific sensitivities for each cancer. Within chronic lymphocytic leukemia (CLL), responses to 62% of drugs were associated with 2 or more mutations, and linked the B cell receptor (BCR) pathway to trisomy 12, an important driver of CLL. Based on drug responses, the disease could be organized into phenotypic subgroups characterized by exploitable dependencies on BCR, mTOR, or MEK signaling and associated with mutations, gene expression, and DNA methylation. Fourteen percent of CLLs were driven by mTOR signaling in a non-BCR-dependent manner. Multivariate modeling revealed immunoglobulin heavy chain variable gene (IGHV) mutation status and trisomy 12 as the most important modulators of response to kinase inhibitors in CLL. Ex vivo drug responses were associated with outcome. This study overcomes the perception that most mutations do not influence drug response of cancer, and points to an updated approach to understanding tumor biology, with implications for biomarker discovery and cancer care.Peer reviewe

Real-world evidence for preventive effects of statins on cancer incidence: a trans-atlantic analysis

BACKGROUND: Numerous clinical trials have considered the potential linkages between statins and cancer. Despite some evidence for reduced mortality associated with statin use, the results thus far have been somewhat inconclusive and not easily comparable, thus hampering the emergence of a consensus. We suspect that this uncertainty would be reduced, and greater clarity achieved (e.g. regarding clinical best practices and standards-of-care), were we to have a reliable, causal biomarker that could help identify those individual patients who might benefit from statin use during cancer treatment. METHODS AND FINDINGS: In the joint experimental and statistical analysis reported here, we assessed the inhibitory potential of various statins on the expression of a tumor enhancer known as MACC1, taking into account the molecular functions of this key metastasis-associated protein. To assess any effects of statins in cancer prevention (observationally), we also performed a retrospective, two-center, nested case-control study, focusing on medical centers in Berlin, Germany and Virginia, USA. Among nearly a half-million patient visits, over a decade-long period, cancer patients were identified and analyzed in comparison to patients without cancer diagnoses. Odds ratios (OR) and hazard ratios (HR) for cancer were computed for patients with and without statin intake, accounting for potential confounders. Finally, we also extended these analyses of our trans-Atlantic cohort by utilizing real-world data from 132,072 cancer patients with statins available on the TriNetX platform. Experimental work revealed that statins inhibit MACC1 mRNA levels and protein expression, resulting in reduced MACC1-induced phenotypic functions, such as motility and proliferation. Moreover, we found that statins restrict colorectal cancer (CRC) growth and metastasis in xenografted mice. The cohort data that we gathered at the German and U.S. centers enabled analysis of 53,113 cancer patients and matched controls. These were extracted, aggregated, and 1:1 matched (by age/gender) in order to build propensity-score matched sub-cohorts, to mitigate confounder bias. Based on this real-world evidence (RWE), we found that atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin and simvastatin were associated with a 50% reduced overall risk for developing cancer (OR 0.5, CI 0.48-0.51). The strongest association of reduced cancer risk was found for (i) liver cancer (OR 0.35, 0.29-0.43), (ii) secondary neoplasms of respiratory and digestive organs (OR 0.42, 0.34-0.45), and (iii) colorectal cancer (OR 0.44, 0.39-0.5). The effect of atorvastatin (OR 0.3, 0.28-0.32) exceeded other considered statins, even after exclusion of aspirin as the strongest confounder (OR 0.63, CI 0.57-0.7). Additionally, we note that those patients taking statins have a 38% decreased risk of death (HR 0.64, 0.48-0.86). CONCLUSIONS: Our data, which offer evidence for cancer-preventative and anti-metastatic effects of statins, lead us to suggest that these medications should be considered in treating some types of cancers. In addition, MACC1 may serve as a potentially helpful biomarker for purposes of patient stratification (and personalized treatment). A more definitive test of these proposed ideas could come from prospective, randomized clinical trials

Subversion of phosphoinositide metabolism by intracellular bacterial pathogens

International audiencePhosphoinositides are short-lived lipids, whose production at specific membrane locations in the cell enables the tightly controlled recruitment or activation of diverse cellular effectors involved in processes such as cell motility or phagocytosis. Bacterial pathogens have evolved molecular mechanisms to subvert phosphoinositide metabolism in host cells, promoting (or blocking) their internalization into target tissues, and/or modifying the maturation fate of their proliferating compartments within the intracellular environment