Institut des Hautes Études Scientifiques

TPS857 Background: While the most frequently mutated solid tumor oncogenes, RAS and RAF , function via aberrant RAF dimerization, approved BRAF inhibitors are only active against mutated BRAF monomers and approved KRAS G12C inhibitors are ineffective for patients with RAS non-G12C tumors. There is a high unmet clinical need for RAF inhibitors that target a broad spectrum of mutated RAF and RAS proteins in solid tumor malignancies. S241656 (previously BDTX-4933) is an oral, CNS-penetrant small-molecule inhibitor engineered to suppress oncogenic K/H/NRAS and class I/II/III BRAF signaling, while avoiding paradoxical MAPK activation, thus creating a broad therapeutic window. Pre-clinical studies demonstrated tumor regression in multiple xenograft models, supporting first-in-human evaluation. The objective of this trial is to evaluate the safety, PK and PD parameters, and antitumor efficacy of S241656. Methods: This phase 1/2 dose escalation (DE) (part 1) and dose optimization and expansion (part 2) study (NCT05786924) will enroll patients in several settings who are aged ≥18 years, ECOG 0/1 who meet the following cohort-related criteria. The BOIN method is used for DE. Gastrointestinal (GI) cancers: Patients with relapsed/refractory advanced GI cancers with selected RAS or RAF alterations who have received at least 1 prior line of standard of care therapy will be enrolled into a monotherapy DE cohort and combination DE cohorts with 2nd line gemcitabine/nab-paclitaxel (PDAC patients) and with 2nd line investigator choice 5FU doublet and anti-EGFR therapy (cetuximab or panitumumab) (CRC patients). After selection of a dose, monotherapy dose expansion cohorts will enroll patients with (a) PDAC; (b) CRC; and (c) biliary tract cancer. NSCLC: Patients with relapsed/refractory advanced NSCLC with RAS or RAF alterations who have received at least one prior line of standard of care therapy will be enrolled into monotherapy DE cohorts. After selection of a dose in DE and/or dose optimization, expansion arms will enroll patients with (a) KRAS non-G12C alterations; (b) BRAF alterations (all classes); (c) KRAS G12C alterations post-progression on G12C targeted therapy; and (d) active CNS metastasis. Other Solid Tumors: Patients with relapsed/refractory advanced other non-NSCLC or non-GI solid tumors with RAS or RAF alterations who have received at least 1 prior line of standard of care therapy will be enrolled into a monotherapy DE cohort. All patients will provide blood and FFPE tumor samples for correlative analyses. The primary objective is safety and tolerability. Secondary endpoints include anti-tumor efficacy, PK studies, and ctDNA analysis. As of September 2025, 23 patients are enrolled. Enrollment is ongoing and the trial is opening more sites in the US, Australia, EU, UK, China, and Japan. Clinical trial information: NCT05786924 .

We study the scattering of boson-star binaries, taking into account three effects: point-mass gravitational, tidal, and short-range scalar-field interactions. We compare analytic results to the scattering angle extracted from four sequences of numerical-relativity simulations at fixed energy and varying impact parameter. The very good agreement exhibits the attractive (repulsive) effect of in-phase (out-of-phase) binaries, wich dominates at small impact parameters. We thus obtain the first effective-one-body potential, central for the construction of analytic gravitational-wave templates.

Reliable prediction and prevention of adverse drug reactions (ADRs) remains a key challenge in the development of new medicines. Advanced mathematical and computational modelling approaches, which incorporate cutting-edge mechanistic understanding of ADRs in concert with systematically collected data addressing knowledge gaps, are integral components of model-informed drug discovery and development (MID3). These approaches provide a precise, quantitative framework for predicting and mitigating safety risks in the earliest phases of drug development. Here, we highlight recent developments in the burgeoning field of quantitative systems toxicology (QST), including insights into the current state-of-the-art, as well as outcomes from the Innovative Medicines Initiative (IMI) 2 TransQST project. QST models that describe the disruption of cardiovascular, gastrointestinal, hepatic and renal physiological functions following drug exposure are presented, along with recommendations for their application in drug discovery and development.

Abstract This article proposes a new way of deriving mean-field exponents for the weakly self-avoiding walk model in dimensions $$d>4$$ d > 4 . Among other results, we obtain up-to-constant estimates for the full-space and half-space two-point functions in the critical and near-critical regimes. A companion paper proposes a similar analysis for spread-out Bernoulli percolation in dimensions $$d>6$$ d > 6 [10].

Building on Toën’s work on affine stacks, we develop a certain homotopy theory for schemes, which we call “unipotent homotopy theory.” Over a field of characteristic p > 0 p>0 , we prove that the unipotent homotopy group schemes π i U ( ⋅ ) \pi _i^{\mathrm {U}}(\,\cdot \,) introduced in our paper recover the unipotent Nori fundamental group scheme (see M. V. Nori [Compositio Math. 33 (1976), pp. 29–41]), the p p -adic étale homotopy groups (see M. Artin and B. Mazur [ Etale homotopy , Springer-Verlag, Berlin-New York, 1969]), as well as certain formal groups introduced by Artin and Mazur [Ann. Sci. École Norm. Sup. (4) 10 (1977), pp. 87–131]. We prove a version of the classical Freudenthal suspension theorem as well as a profiniteness theorem for unipotent homotopy group schemes. We also introduce the notion of a formal sphere and use it to show that for Calabi–Yau varieties of dimension n n , the group schemes π i U ( ⋅ ) \pi _i^{\mathrm {U}}(\,\cdot \,) are derived invariants for all i ≥ 0 i \ge 0 ; the case i = n i=n is related to recent work of Antieau and Bragg [Algebr. Geom. 9 (2022), pp. 364–399] involving topological Hochschild homology. Using the unipotent homotopy group schemes, we establish a correspondence between formal Lie groups and certain higher algebraic structures.