- |||||||||| Lumakras (sotorasib) / Amgen
Genialis (Section 44) - Mar 5, 2024 - Abstract #AACR2024AACR_7703;
The performance characteristics of ResponderID
- |||||||||| Ibrance (palbociclib) / Pfizer, Nutlin-3 / EMD Serono
Genetically engineered human lung organoid models for lung cancer evolution study (Section 11) - Mar 5, 2024 - Abstract #AACR2024AACR_7377;
First, we knocked out TP53 of the airway organoids, selected by Nutlin-3a, an MDM2 antagonist, for 3-4 weeks, demonstrating 88-89% editing efficiencies calculated from Sanger sequencing results...We used Palbociclib, a CDK4/6 inhibitor, to enrich the mutated cells...This is the first work constructing the SCLC development model from the normal human airway organoid. By sequentially single-cell sequencing this organoid model changing to tumorous condition, we can capture the multi-omics landscape during the initial evolution of SCLC.
- |||||||||| Lumakras (sotorasib) / Amgen, DCC-3116 / Deciphera
Inhibition of ULK and KRASG12C control tumor growth in preclinical models of lung cancer (Section 14) - Mar 5, 2024 - Abstract #AACR2024AACR_7053;
Consequently, we have generated genetically engineered mouse models (GEMMs) of KRASG12C-driven lung cancer in which LKB1 is silenced to further investigate the role of LKB1 in the autophagy response of KRASG12C-driven lung cancers to pathway-targeted blockade of oncogenic KRAS signaling. We have treated KRASG12C-driven GEMMs with sotorasib and/or DCC-3116 to test the sensitivity of lung tumors to these treatment options.
- |||||||||| Ibrance (palbociclib) / Pfizer
Nanoparticle-mediated combination therapy to synergistically harness Type I interferons and senescence in the pancreatic tumor microenvironment (Section 3) - Mar 5, 2024 - Abstract #AACR2024AACR_6917;
Here, we hypothesize that combination therapy of proinflammatory NPs with tumor senescence-inducing RAS inhibitors, tremetinib and palbociclib, will not only augment CD8+ T cell recruitment to the TME but enhance their sustained activation by mitigating local immunosuppression...In conclusion, these findings strongly corroborate the use of this NP-based system as a platform therapy for similar drugs and across other aggressive cancers. They also strongly make the case for the rational design of combination therapies to achieve synergistic therapeutic outcomes with minimal systemic toxicities.
- |||||||||| MTAP deleted cancer targeting synthetic lethal therapeutic / Ryvu Therap
Discovery of novel MTA-cooperative PRMT5 inhibitors as targeted therapeutics for MTAP-deleted cancers (Section 24) - Mar 5, 2024 - Abstract #AACR2024AACR_6897;
The correlation between compound exposure and on-target effect was confirmed in PK/PD and efficacy studies. Taken together, these studies confirm that MTA cooperative PRMT5 inhibitors exert strong synthetic lethal phenotype in MTAP deleted cancers and offer an exciting therapeutic opportunity for a large patient population.
- |||||||||| MTAP loss alters the epigenetic landscape and demonstrates superior therapeutic sensitivity to concomitant PRMT5 and PARP inhibition in cholangiocarcinoma (Section 22) - Mar 5, 2024 - Abstract #AACR2024AACR_6873;
P1/2
This renders selective targeting of MTAP null tumors with agents (MRTX1719, AMG193, TNG462, TNG908) targeting MTA bound PRMT5 (PRMT5:MTA), while sparing surrounding normal MTAP wild-type (WT) tissue...To address this pressing need, we co-treated CCA cell lines with MRTX1719 and PARP inhibitor olaparib...Similar differences in proportion of splicing events were also observed in MTAP loss CCA patient derived xenografts as compared to WT models. Collectively, these data implicate MTAP to be a crucial player in modulation of the chromatin and splicing events that may drive therapeutic response to PRMT5 inhibition.
- |||||||||| Lorbrena (lorlatinib) / Pfizer, Tagrisso (osimertinib) / AstraZeneca, Lumakras (sotorasib) / Amgen
Unraveling the vulnerabilities of targeted therapy-tolerant persister cells in NSCLC (Section 27) - Mar 5, 2024 - Abstract #AACR2024AACR_6792;
The metabolic transition in drug tolerant persister cells may serve as a critical adaptive resistance mechanism to provide a survival advantage under targeted therapy-induced stress. Understanding this metabolic shift may lead to new treatments that aim to prevent or delay the onset of acquired resistance in NSCLC.
- |||||||||| DXC004A / Hangzhou DAC Biotech
DXC004A, a novel EGFR antibody-tubulysin analog conjugate demonstrated potential to broaden therapeutic opportunities for non-small cell lung cancer (Section 23) - Mar 5, 2024 - Abstract #AACR2024AACR_6709;
A phase 2 clinical trial has confirmed that Nimotuzumab combined with concurrent chemoradiation therapy (radiation concurrent with docetaxel and cisplatin, CCRT) was well tolerated for locally advanced squamous cell lung cancer...Moreover, the combination of DXC004A with Cisplatin exhibited significantly better activities than that of Nimo-CCRT combination, DXC004A or cisplatin alone, in vitro and in vivo, which might solve the predicament of poor efficacy of Nimo-CCRT combination therapy. This synergy results suggested that DXC004A plus cisplatin would possibly be a new adjuvant therapy for non-small cell lung cancer in further clinical studies.
- |||||||||| Organoids to predict treatment response in metastatic colorectal cancer (OPTIC) (Section 45) - Mar 5, 2024 - Abstract #AACR2024AACR_6462;
OPTIC will enhance the clinical application of PDOs by defining thresholds for PDO sensitivity and analyzing the diagnostic power for different treatments. To enable personalized treatment in clinical practice, PDO screening should guide mCRC treatment and result in enhanced chance of response and reduced over- and mistreatment.
- |||||||||| Ibrance (palbociclib) / Pfizer
Subcellular MLH1 protein as first in class biomarker for CDK4/6 response in endocrine resistant ER+/HER2- breast cancer (Section 44) - Mar 5, 2024 - Abstract #AACR2024AACR_6420;
Moreover, we demonstrated increased sensitivity to palbociclib, a CDK4/6 inhibitor, in experimental model systems in vitro and in vivo and in clinical trial data...Simultaneously, a lack of predictive markers can result in missed opportunities of presenting patients likely to relapse on standard care with personalized alternative therapeutic strategies. Based on our findings, cytoplasmic MLH1 may serve as first in-class biomarker for CDK4/6 response in ER+/HER2- patients.
- |||||||||| Lumakras (sotorasib) / Amgen
A computational initiative to determine the role of dietary polyphenols against oncogenic KRAS mutants (Section 20) - Mar 5, 2024 - Abstract #AACR2024AACR_6390;
These findings have important implications for patient selection and personalized treatment strategies in such patients. Computer-aided drug designing performed here aided the identification of natural dietary polyphenolic inhibitors as potential drug candidates exhibiting stable binding dynamics like Sotorasib, which thus awaits validation through further in-vitro analyses in inhibiting KRAS-driven tumorigenesis.
- |||||||||| Ibrance (palbociclib) / Pfizer
AI-enabled hit selection of drug screening on human pancreatic cancer organoids (Section 36) - Mar 5, 2024 - Abstract #AACR2024AACR_6305;
The data suggests that the compound treatment Palbociclib 50uM has significant cytotoxicity effects similar to the positive control, which is consistent with the traditional live/dead analysis. The AI approach demonstrates feasibility to perform drug screening in a robust and un-biased data analysis approach.
- |||||||||| Prolia (denosumab) / Amgen
In vitro assays for investigating the effects of cancer therapeutics on bone (Section 13) - Mar 5, 2024 - Abstract #AACR2024AACR_6004;
Denosumab was added in the cultures at day 0, and tartrate-resistant acid phosphatase isoform 5b (TRACP 5b) activity was measured from the culture medium collected at day 7...BMP-2 and E2 stimulated osteoblast differentiation and activity indicated by the increase in ALP activity, PINP and calcium levels. We conclude that these culture systems can be used for studying the effects of cancer therapeutics and identifying new potential compounds affecting the disease process of bone metastases with different mechanisms of action.
- |||||||||| Vectibix (panitumumab) / Amgen
Cancer associated fibroblasts targeted photoimmunotherapy improves drug delivery (Section 13) - Mar 5, 2024 - Abstract #AACR2024AACR_5981;
The ECM, including CAFs, poses a barrier to drug delivery. Our findings indicate that FAP-PIT can effectively enhance drug penetration in CAF-rich tumors, presenting a novel therapeutic strategy to overcome drug resistance.
- |||||||||| Ibrance (palbociclib) / Pfizer
Palbociclib as a novel therapeutic for desmoplastic small round cell tumor (Section 11) - Mar 5, 2024 - Abstract #AACR2024AACR_5920;
Palbociclib treatment was effective not only in vitro but also in vivo where it significantly reduced tumor growth in two xenograft models of DSRCT. Given these novel findings and palbociclib's previous approval by the FDA for the treatment of breast cancer, we advance palbociclib as an exciting DSRCT therapy that warrants urgent clinical investigation.
- |||||||||| AIG01012 / AIGEN Sci
Discovery of a novel SOS1 inhibitor, AIG01012, targeting pan-KRAS mutant cancers (Section 28) - Mar 5, 2024 - Abstract #AACR2024AACR_5476;
In summary, utilizing our human-in-the-loop (HITL) AI platform, AIGEN ChemTailor, we have efficiently derived AIG01012 as a potent SOS1 inhibitor that targets a wide range of KRAS interactions. With its notable in vitro and in vivo outcomes, AIG01012 is set for further exploration and prospective clinical trials as a significant contender in KRAS-targeted cancer treatments.
- |||||||||| MRTX1133 / BMS, Lumakras (sotorasib) / Amgen
In vivo and in vitro experience with novel direct Pan-RAS inhibitors (Section 28) - Mar 5, 2024 - Abstract #AACR2024AACR_5472;
They exhibit distinct RAS signal inhibition patterns compared to these agents. They can also co-operate with the clinical agents and reduce drug resistance effects.
- |||||||||| Krazati (adagrasib) / BMS, CYRS1645 / Yuhan Corp, Lumakras (sotorasib) / Amgen
Discovery of a potent, selective, and orally available small molecule for disruption of the SOS1-RAS interaction (Section 28) - Mar 5, 2024 - Abstract #AACR2024AACR_5465;
It has demonstrated remarkable synergy effects with RTK/RAS/MAPK pathway inhibitors, significantly impeding the growth of tumors carrying KRAS or EGFR mutations in vivo. Overall, our development candidate has demonstrated significant therapeutic potential in combination with inhibitors targeting the RTK/RAS/MAPK pathway for cancers bearing activating mutations in this pathway.
- |||||||||| Ibrance (palbociclib) / Pfizer
Learning to target CDK4/6 inhibitor resistance via a breast cancer-specific atlas of cellular mechanisms (Section 26) - Mar 5, 2024 - Abstract #AACR2024AACR_5375;
Leveraging a breast cancer-specific atlas of cellular architecture, our framework learned genetic mechanisms of CDK4/6 inhibitor resistance from a high-throughput phenotypic screen of ~700 cell lines treated with the clinical CDK4/6 inhibitor palbociclib...Finally, while monotherapy inhibition of the target and CDK4/6 induced cell cycle arrest, the combination strongly induced apoptosis in cell lines resistant to CDK4/6 inhibitors. These results highlight how computational deconvolution of tumor resistance mechanisms enable algorithmic identification of therapeutic options to target treatment-resistant cell populations.
- |||||||||| Piqray (alpelisib) / Novartis, Ibrance (palbociclib) / Pfizer
Endocrine resistance genes driving cross-resistance to current combination therapies in HR-positive breast cancer (Section 26) - Mar 5, 2024 - Abstract #AACR2024AACR_5370;
Tamoxifen resistance genes BCAR3, BCAR4 and EGFR show various degrees of cross-resistance to other breast cancer treatments. It might be worthwhile to evaluate these genes or their associated biological pathways as predictive biomarkers for cross-resistance in HR+ breast cancer patients treated with the mentioned (combination) therapies.
- |||||||||| Erbitux (cetuximab) / Eli Lilly, EMD Serono
Characterization of EGFR ectodomain mutation in acquired resistance to cetuximab in colorectal cancer (Section 26) - Mar 5, 2024 - Abstract #AACR2024AACR_5352;
Further structural, and functional characterization is underway for this ectodomain mutation that confers resistance to cetuximab and will be shared during the meeting. These findings necessitate the need for additional treatment strategies for a subset of subjects with mCRC who do not respond to treatment with cetuximab/panitumumab and MM-151.
- |||||||||| Blincyto (blinatumomab) / Astellas, Amgen
A novel long acting pegylated T cell engager targeting CD3 and cd19 with effective tumor killing and no potential CRS risk in CD19+ hematologic malignancies (Section 23) - Mar 5, 2024 - Abstract #AACR2024AACR_5326;
However, Blinatumomab, a bispecific T cell engager of CD3/CD19, has disadvantages in clinical setting due to the adverse pharmacokinetics (PK), which resulted in less than 2 hours of in vivo elimination half-life, neurotoxicity, and cytokine release syndrome...We postulated that the lower CD3 affinity of JY108 most probably resulted in the decoupling of the signaling for activating the gene expression of cytokines from the secretion of the polarized lytic granules by T cells, which resulted in a much milder T cell activation by JY108. Currently, JY108 is a phase I trial candidate and awaits further evaluations.
- |||||||||| MRTX1133 / BMS, Lumakras (sotorasib) / Amgen
The in vivo Hollow Fiber model is a valuable tool in drug development of selective KRas inhibitors (Section 22) - Mar 5, 2024 - Abstract #AACR2024AACR_5269;
AMG510 (Sotorasib), a drug approved for tumors with a G12C Kras mutation, and MRTX1133, which is currently in clinical phase and shows activity in tumors with a G12D Kras mutation, were screened for their inhibitory effect on the pancreatic tumor cells MiaPaCa-2 (G12C Kras mutation), AsPC-1 (G12D Kras mutation) and BxPC-3 (wt Kras) in the in vivo Hollow Fiber model in female NMRI nude mice. While the growth of BxPC-3 tumor cells was not affected by either inhibitor, the growth of AsPC-1 tumor cells in particular was selectively and significantly inhibited by MRTX1133.In summary, the in vivo Hollow Fiber model is a fast and cost-effective model that can play an prominent role in drug development as a link between in vitro and in vivo xenograft studies by providing rapid and transferable evidence for in vivo efficacy.
|
