-
Mashup Score: 16
Abstract. First-generation KRAS G12C inhibitors, such as sotorasib and adagrasib, are limited by the depth and duration of clinical responses. One potential explanation for their modest clinical activity is the dynamic “cycling” of KRAS between its GDP- and GTP-bound states, raising controversy about whether targeting the GDP-bound form can fully block this oncogenic driver. We herein report D3S-001, a next generation GDP-bound G12C inhibitor with faster target engagement (TE) kinetics, depletes cellular active KRAS G12C at nanomolar concentrations. In the presence of growth factors, such as EGF and HGF, the ability of sotorasib and adagrasib to inhibit KRAS was compromised whereas the TE kinetics of D3S-001 was nearly unaffected, a unique feature differentiating D3S-001 from other GDP-bound G12C inhibitors. Furthermore, the high covalent potency and cellular TE efficiency of D3S-001 contributed to robust anti-tumor activity preclinically and translated into promising clinical activity
Source: aacrjournals.orgCategories: General Medicine News, Hem/OncsTweet
-
Mashup Score: 27
Abstract. RAF inhibitors have transformed treatment for BRAF V600-mutant cancer patients, but clinical benefit is limited by adaptive induction of ERK signaling, genetic alterations that induce BRAF V600 dimerization, and poor brain penetration. Next-generation pan-RAF dimer inhibitors are limited by narrow therapeutic index. PF-07799933 (ARRY-440) is a brain-penetrant, selective, pan-mutant BRAF inhibitor. PF-07799933 inhibited signaling in vitro, disrupted endogenous mutant-BRAF:wild-type-CRAF dimers, and spared wild-type ERK signaling. PF-07799933 ± binimetinib inhibited growth of mouse xenograft tumors driven by mutant BRAF that functions as dimers and by BRAF V600E with acquired resistance to current RAF inhibitors. We treated patients with treatment-refractory BRAF-mutant solid tumors in a first-in-human clinical trial (NCT05355701) that utilized a novel, flexible, pharmacokinetics-informed dose escalation design that allowed rapid achievement of PF-07799933 efficacious concentra
Source: aacrjournals.orgCategories: General Medicine News, Onc News and JournalsTweet
-
Mashup Score: 3Warburg Effect Reshapes Tumor Immunogenicity - 1 day(s) ago
Abstract. Tumor cells rewire their metabolism to fulfill the demands of highly proliferative cells. This changes cellular metabolism to adapt to fuel and oxygen availability for energy production and to increase the synthesis capacity of building blocks for cell division and growth. In addition, the metabolic shift also modulates the immunogenicity of the tumor cells. Recently, Mahmood and colleagues reported a connection between mitochondrial DNA mutations in cancer cells and their response to immunotherapy in a mouse model of melanoma.
Source: aacrjournals.orgCategories: General Medicine News, Onc News and JournalsTweet
-
Mashup Score: 31Molecular Determinants of Sensitivity to Polatuzumab Vedotin in Diffuse Large B Cell Lymphoma - 1 day(s) ago
Abstract. Polatuzumab Vedotin (Pola-V) is an antibody-drug conjugate directed to the CD79B subunit of the B cell receptor (BCR). When combined with conventional immunochemotherapy, Pola-V improves outcomes in DLBCL. To identify determinants of Pola-V sensitivity, we used CRISPR-Cas9 screening for genes that modulated Pola-V toxicity for lymphomas or the surface expression of its target, CD79B. Our results reveal the striking impact of CD79B glycosylation on Pola-V epitope availability on the lymphoma cell surface and on Pola-V toxicity. Genetic, pharmacological, and enzymatic approaches that remove sialic acid from N-linked glycans enhanced lymphoma killing by Pola-V. Pola-V toxicity was also modulated by KLHL6, an E3 ubiquitin ligase that is recurrently inactivated in germinal center derived lymphomas. We reveal how KLHL6 targets CD79B for degradation in normal and malignant germinal center B cells, thereby determining expression of the surface BCR complex. Our findings suggest precis
Source: aacrjournals.orgCategories: General Medicine News, Hem/OncsTweet
-
Mashup Score: 1
Abstract. More than ever, scientific progress in cancer research hinges on our ability to combine datasets and extract meaningful interpretations to better understand diseases and ultimately inform the development of better treatments and diagnostic tools. To enable the successful sharing and use of big data, the NCI developed the Cancer Research Data Commons (CRDC), providing access to a large, comprehensive, and expanding collection of cancer data. The CRDC is a cloud-based data science infrastructure that eliminates the need for researchers to download and store large-scale datasets by allowing them to perform analysis where data reside. Over the past 10 years, the CRDC has made significant progress in providing access to data and tools along with training and outreach to support the cancer research community. In this review, we provide an overview of the history and the impact of the CRDC to date, lessons learned, and future plans to further promote data sharing, accessibility, int
Source: aacrjournals.orgCategories: General Medicine News, Onc News and JournalsTweet
-
Mashup Score: 28Enhanced Molecular Response in Myeloproliferative Neoplasms with Complete JAK2V617F Inhibition - 1 day(s) ago
Summary:. Dunbar, Bowman, and colleagues present here a novel genetic mouse model with inducible and reversible expression of the JAK2V617F mutation in the endogenous locus. Results from this study clearly demonstrate an absolute requirement for myeloproliferative neoplasm–initiating cells for this mutation in their survival and imply that more efficacious inhibitors could be curative for these patients even in the setting of additional cooperating mutations.See related article by Dunbar et al., p. 737 (8).
Source: aacrjournals.orgCategories: General Medicine News, Hem/OncsTweet
-
Mashup Score: 6
Summary. Combination immune-checkpoint inhibition with chemotherapy is a clinical standard, yet concurrent administration may limit the full benefit of immunotherapy by blunting the proliferation and differentiation of CD8 T cells. Identifying patients in whom sequential chemo-immunotherapy or immunotherapy alone is feasible should be a priority to optimize long-term outcomes.See related article by Mariniello et al., p. 1833
Source: aacrjournals.orgCategories: General Medicine News, Onc News and JournalsTweet
-
Mashup Score: 5A Novel Approach for Conducting a Catchment Area Analysis of Breast Cancer by Age and Stage for a Community Cancer Center - 1 day(s) ago
AbstractBackground:. The U.S. Preventive Services Task Force recently issued an updated draft recommendation statement to initiate breast cancer screening at age 40, reflecting well-documented disparities in breast cancer–related mortality that disproportionately impact younger Black women. This study applied a novel approach to identify hotspots of breast cancer diagnosed before age 50 and/or at an advanced stage to improve breast cancer detection within these communities.Methods:. Cancer registry data for 3,497 women with invasive breast cancer diagnosed or treated between 2012 and 2020 at the Helen F. Graham Cancer Center and Research Institute (HFGCCRI) and who resided in the HFGCCRI catchment area, defined as New Castle County, Delaware, were geocoded and analyzed with spatial intensity. Standardized incidence ratios stratified by age and race were calculated for each hotspot.Results:. Four hotspots were identified, two for breast cancer diagnosed before age 50, one for advanced b
Source: aacrjournals.orgCategories: General Medicine News, Onc News and JournalsTweet
-
Mashup Score: 3
Convergence Science | Cancer Research | American Association for Cancer Research .aacrcontent { display: flex; flex-direction: row; justify-content: space-between; align-items: stretch; } .intro { margin-top: 26px; font-size: 1.2em; } /* ****************** LEFT SIDE ****************** */ .left-side{ color: #000000; background-color: #fff; max-width: 710px; margin-right: 26px; } .left-side h3{ margin-bottom: 26px; } .node { line-height: 1.2em; margin-left: 12px; } .node2 {line-height: 1.0em; }…
Source: aacrjournals.orgCategories: General Medicine News, Onc News and JournalsTweet
-
Mashup Score: 2Sotorasib Is a Pan-RASG12C Inhibitor Capable of Driving Clinical Response in NRASG12C Cancers - 2 day(s) ago
Sotorasib and other selected KRASG12C inhibitors leverage differential dependence on switch-II pocket binding at amino acid position 95 to target all RASG12C isoforms, which has critical implications for the treatment of NRASG12C- or HRASG12C-mutant tumors.
Source: aacrjournals.orgCategories: General Medicine News, Onc News and JournalsTweet
New online @CD_AACR - KRAS G12C inhibitor from D3 Bio (🇨🇳): D3S-001, a KRAS G12C inhibitor with rapid target engagement kinetics, overcomes nucleotide cycling and demonstrates robust preclinical and clinical activities https://t.co/SymQ0WEE4c https://t.co/PqXYzNbWvS