Wellspring Biosciences (United States)

A new patient satisfaction measure called the Radiation Oncology Patient Satisfaction (ROPS) questionnaire is used in this study to measure satisfaction data for radiation oncology in private practice. Limitations of existing literature on patient satisfaction demonstrated a need to develop a questionnaire that was more tailored to analyze patient satisfaction among those utilizing private oncology centers within the U.S. healthcare system. This need was met by this study’s development of the ROPS questionnaire, which was a variation of 2 existing constructs that are presented in the text. The questionnaire was fielded among patients at a private cancer radiation treatment clinic in Florida (n = 950). Data analysis tested the psychometric properties of our revised construct and its predictive validity for 2 patient satisfaction outcomes: (1) likelihood of recommending this treatment center to family members/close friends and (2) overall satisfaction with treatment. Each of the ROPS variables were found to make a legitimate contribution to evaluating patients’ overall satisfaction with radiation treatment. Findings indicated organizational setting was of vital importance when conducting patient- centered research on satisfaction. Treatment factors in ROPS can be adjusted to measure satisfaction with chemotherapy or other modalities in addition to radiation treatment. Authors recommend radiation oncology clinics regularly monitor patient satisfaction, especially if/when they experience organizational changes, such as when a new physician joins the practice or if/when the national or local landscape undergoes significant shifts in norms and expectations like we have seen happen with COVID-19.

Abstract Background: CXCL12 is a negative prognostic factor for head & neck (HNSCC) and pancreatic (PDCA) cancers, among others. Its receptor, CXCR4, is a negative prognostic factor in lymphoma/leukemia. CXCR4 signals in part through RAS species, and the expression of CXCL12 and CXCR4 appears to be itself regulated by farnesylated proteins. We provide evidence that targeting the CXCL12/CXCR4 pathway with the farnesyltransferase inhibitor tipifarnib translates to long term clinical benefit. Methods: Next generation sequencing and analyses of gene expression were conducted in tumor samples from squamous cell carcinoma, lymphoma, and acute myeloid leukemia (AML) patients treated in tipifarnib trials (studies KO-TIP-001, KO-TIP-002, CTEP20), and complemented with analyses of related tumor gene expression databases in TCGA and GEO. Results: Activating HRAS mutations in HNSCC and KRAS mutations in PDCA were mutually exclusive with CXCL12 expression, consistent with a role for RAS downstream from CXCR4. Contrary to KRAS and NRAS, HRAS is exclusively farnesylated, and treatment with tipifarnib in patients (pts) with advanced HNSCC tumors with a HRAS mutation variant allele frequency (VAF) >20% resulted in 8 partial responses (PR) in 14 pts. Two complete responses (CR), 3 PRs and 4 disease stabilizations (90% clinical benefit) were observed in 10 pts with relapsed/refractory peripheral T cell lymphoma overexpressing CXCL12. Decreases in plasma CXCL12 levels during treatment were observed. Seven CRs were observed in 11 elderly/unfit AML pts overexpressing CXCL12 in bone marrow (NRAS wt or unknown). Ex vivo treatment of bone marrow stromal cell cultures with tipifarnib decreased secretion of CXCL12. Finally, based on the reported relationship between CXCL12 expression and the suppression of pain in PDCA, we conducted a retrospective analysis of a phase 3 study of gemcitabine plus tipifarnib (GT) in advanced PDCA. Notably, absence of abdominal pain at study entry was associated with higher median survival in the GT arm (no pain, pain): 10.2 vs 5.9 months, HR=0.52, p<0.0001, whereas no significant effect was observed in the control arm: 6.1 vs 6.1 months. PDCA with <7% VAF of KRAS mutation (~30% PDCA pts) overexpressed CXCL12. Conclusions: The mechanism of action of tipifarnib appears to involve targeting the CXCL12/CXCR4 pathway and demonstrates a crucial association with the tumor microenvironment and objective clinical responses. Citation Format: Antonio Gualberto, Catherine Scholz, Vishnu Mishra, Matthew R. Janes, Linda Kessler, Eric Van Cutsem, Alan L. Ho, Thomas Witzig. Mechanism of action of the farnesyltransferase inhibitor, tipifarnib, and its clinical applications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT191.

KRAS-mutant lung cancers have been recalcitrant to treatments including those targeting the MAPK pathway. Covalent inhibitors of KRAS p.G12C allele allow for direct and specific inhibition of mutant KRAS in cancer cells. However, as for other targeted therapies, the therapeutic potential of these inhibitors can be impaired by intrinsic resistance mechanisms. Therefore, combination strategies are likely needed to improve efficacy.Experimental Design: To identify strategies to maximally leverage direct KRAS inhibition we defined the response of a panel of NSCLC models bearing the KRAS G12C-activating mutation in vitro and in vivo. We used a second-generation KRAS G12C inhibitor, ARS1620 with improved bioavailability over the first generation. We analyzed KRAS downstream effectors signaling to identify mechanisms underlying differential response. To identify candidate combination strategies, we performed a high-throughput drug screening across 112 drugs in combination with ARS1620. We validated the top hits in vitro and in vivo including patient-derived xenograft models. Response to direct KRAS G12C inhibition was heterogeneous across models. Adaptive resistance mechanisms involving reactivation of MAPK pathway and failure to induce PI3K-AKT pathway inactivation were identified as likely resistance events. We identified several model-specific effective combinations as well as a broad-sensitizing effect of PI3K-AKT-mTOR pathway inhibitors. The G12Ci+PI3Ki combination was effective in vitro and in vivo on models resistant to single-agent ARS1620 including patient-derived xenografts models. Our findings suggest that signaling adaptation can in some instances limit the efficacy of ARS1620 but combination with PI3K inhibitors can overcome this resistance.

Abstract We describe the biochemical mechanism of the covalent KRASG12C inhibitors ARS-853 and ARS-1620. Activating mutations in KRAS are among the most common mutations found in cancer. The KRASG12C mutation in particular is observed in approximately 15 % of non-small cell lung adenocarcinoma, 3 % of colorectal adenocarcinoma and 1 % of pancreatic adenocarcinoma. Until recently, KRAS had been considered undruggable due to the lack of clearly defined pockets that might support binding of small molecules, and the difficulty of targeting the nucleotide binding site due to the high affinity of GDP and GTP. However several years ago small molecules were discovered that bind an inducible pocket near the switch II region and covalently target the mutated cysteine in KRASG12C, trapping KRASG12C in a nonproductive GDP-bound state. Subsequent optimization of these compounds yielded the recently described inhibitors ARS-853 and ARS-1620, the first compounds that directly inhibit KRAS with high potency in cells and animals. While the biological activity of the inhibitors has been described, the biochemical mechanism of how the compounds achieve potent inhibition remained incompletely understood. We now show through biochemical kinetics studies that the activity of ARS-853 and ARS-1620 is primarily driven by KRAS-mediated catalysis of the chemical step of covalent bond formation with cysteine 12 in KRASG12C, rather than by high reversible binding affinity. The reversible inhibition constant (Ki) for both ARS-853 and ARS-1620 is well above the highest compound concentration tested (64 µM, to avoid solubility limitations), likely in the hundreds of micromolar range, while the rate of the chemical step (kinact) is fast. We confirm by several independent means that there is no detectable reversible binding affinity of the inhibitors for KRAS up to at least 32 µM, and show that the rapid chemical reaction is not due to high inherent reactivity of cysteine 12 in KRAS, nor to high intrinsic reactivity of the inhibitors. The results imply that the inhibitors do bind reversibly to KRAS to enable bond formation, but that binding is weak and primarily serves to orient the electrophile. The KRAS-dependent activation of covalent bond formation of ARS-853 and ARS-1620 with the mutated cysteine 12 is reminiscent of mechanism-based or suicide covalent enzyme inhibition, and explains both the high selectivity of the inhibitors for this cysteine relative to other cellular cysteines, and their potent overall activity despite exhibiting poor reversible affinity. The mechanism described here therefore resolves how an induced, shallow and dynamic pocket that is not expected to support high affinity binding of small molecules can nevertheless be targeted with potent inhibitors, and may be applicable to other targets conventionally considered undruggable. Citation Format: Rasmus Hansen, Ulf Peters, Anjali Babbar, Yuching Chen, Jun Feng, Matthew R. Janes, Liansheng Li, Pingda Ren, Yi Liu, Patrick P. Zarrinkar. Drugging an undruggable pocket: The biochemical mechanism of covalent KRASG12C inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 686.