NRAS G12V

We elucidated the mechanism of action of a potent KRAS G12D inhibitor, MRTX1133. Binding of this inhibitor to the switch-2 pocket causes a complete shift of KRAS G12D towards the "inactive" conformation and prevents binding of effector RAS-binding domain (RBD) at physiological concentrations, by signaling through an allosteric network.

NRAS mutation was found only in the abdominal tumor and was thought to be responsible for malignant progression in the present case. Multiregional comprehensive genetic analysis may lead to discovering novel driver mutations associated with tumorigenesis and targeted therapy.

P1/2, N=8, Suspended, National Cancer Institute (NCI) | N=110 --> 8 | Recruiting --> Suspended

Treatment was ruxolitinib and hydroxyurea...He started dasatinib and decitabine, which resulted in a drop from 28...However, hyperuricemia and renal failure led to a change in regimen and the patient was started on asciminib and ropeginterferon alfa-2b-njft in January 2022...He received cladribine and cytarabine, but was found to have leukemic infiltration of the spinal cord five months later...However, he always maintained a high CALR burden. This patient's mutational profile and disease course argue for the importance of early testing for CALR and BCR-ABL in addition to JAK2 and MPL in the setting of an MPN and for further research into the underlying causes of these overlap conditions.

Contrary to prior assumptions, the G12V NRAS mutant form is sufficient to elicit hepatocarcinogenesis in the mouse. Furthermore, the upregulation of the MAPK cascade was paralleled by the overexpression of DUSP4, DUSP6, and CD133 in vivo and in vitro. Therefore, DUSP4 and DUSP6 might fine-tune the excessive MAPK activation, a mechanism that can potentially be harnessed therapeutically.

Using this method, we demonstrate that primary human AML samples express the single-cell profiles of self-renewal that we previously validated experimentally. SCA-based identification of human self-renewing cells will allow us to interrogate novel transcriptional features of these cells in future studies.

P1/2, N=39, Completed, Gritstone bio, Inc. | Active, not recruiting --> Completed | Trial completion date: Dec 2023 --> Mar 2023 | Trial primary completion date: Dec 2023 --> Mar 2023

P2 | "According to liquid biopsy before second- and third-line therapies, treatment sequences are: FOLFIRI + cetuximab (first-line), FOLFOX + cetuximab (second-line); irinotecan + cetuximab (third-line) in patients with plasma ctDNA RAS/BRAFV600E WT tumors. In patients with RAS/BRAFV600E mutant tumors, second-line is FOLFOX + bevacizumab, while third-line is regorafenib or trifluridine/tipiracil (investigator's choice)... Both tumor tissue- and liquid biopsy-based comprehensive genomic profiling by NGS identify additional molecular alterations, that could be involved in resistance to anti-EGFR monoclonal antibodies, as compared to PCR-based tumor tissue analysis. CAPRI 2-GOIM trial will determine if NGS would allow better selection of RAS/BRAFV600E WT mCRC patients for the most appropriate treatments through three sequential lines of therapies."

P1/2, N=156, Recruiting, Elicio Therapeutics | Not yet recruiting --> Recruiting

P1/2, N=156, Not yet recruiting, Elicio Therapeutics

P1/2, N=39, Active, not recruiting, Gritstone bio, Inc. | Recruiting --> Active, not recruiting | N=144 --> 39

P1/2, N=144, Recruiting, Gritstone bio, Inc. | Trial primary completion date: Dec 2022 --> Dec 2023

Cobimetinib plus Dexamethasone were administered for two 28-day cycles followed by the addition of an Ixazomib, Pomalidomide and Dexamethasone (IPd) backbone therapy for all subsequent treatment cycles until disease progression. After exposure to Cobimetinib, the plasma cell clusters that expressed higher levels of this MAPK signature decreased in proportion relative to clusters with lower expression of MAPK. In summary, here we report on our initial observations of dynamic transcriptional changes in specific immune and myeloma cell compartments that are associated with targeting the MAPK pathway in the MyDrug C1 sub-protocol.

Patient was started on a bortezomib-based regimen (VCD), and radiation therapy (8 Gy) was delivered on the left knee and both ankles...High dose melphalan followed by ASCT is planned in the near future. Our case underlines the fact that MM can occasionally manifest at diagnosis with an unusual pattern of bone involvement with a predominance in the distal limbs instead of the axial skeleton. In order to start therapy in a timely manner, biopsy of the lesion should not be postponed since BM aspiration may fail to establish the diagnosis.

We replaced the endogenous NRASG12D gene with a tetracycline-inducible and dose-responsive NRASG12V transgene...This system provides a new model to study RAS oncogene addiction and RAS-induced self-renewal in AML. Implications: Different levels of activated NRAS may exert distinct effects on proliferation and self-renewal.

Experimental anti-tumour Benzoprims, analogues of the anti-malarial drug pyrimethamine, possess anti-tumour activity against metastatic melanoma cells, mainly by inhibiting dihydrofolate reductase (DHFR), a validated target in cancer therapy...Conclusion Benzoprims are most potent in CRC cell lines possessing mutant KRAS G13D . Although their mechanism of action independent of DHFR inhibition is still unclear, downregulation of proteins by SM1235 in HCT116 cells indicate that benzoprims inhibit proteins downstream of RAS.

It is feasible to perform NGS analysis using reference laboratories. There is population of patients, willing to undergo specialized tests. Actionable molecular data information can be collected and utilized for patient care.

Our findings indicate that dual-driver mutations occur in a rare subset of CRC, often within the same tumor cells and across multiple tumor sites. Their presence and a lower rate of allelic imbalance may be related to dose-dependent signaling within the mitogen-activated protein kinase pathway.

In contrast to cancer arising from the thyroid gland, characterized by BRAFV600E as the most common mutation, malignant SO belongs to RAS-like tumors. The downregulation of tumor suppressors and upregulation of DMRT1 might be implicated in the malignant transformation of SO.

P1/2, N=30, Recruiting, Changhai Hospital | Trial completion date: Mar 2023 --> Mar 2025 | Trial primary completion date: Dec 2022 --> Dec 2024

P1/2, N=110, Recruiting, National Cancer Institute (NCI) | Suspended --> Recruiting

We have identified senescence-specific CD4+ T-cells during senescence surveillance. Functional analyses of intrahepatic CD4+ lymphocytes suggest an accumulation of functional Th17 cells during active senescence surveillance. Further analysis of the functional properties of senescencespecific CD4+ T-lymphocytes is on-going.

Here we evaluated matched pre-treatment and post-treatment specimens from 43 patients treated with the KRAS(G12C) inhibitor sotorasib...A subset of patients in our cohort acquired oncogenic KRAS, NRAS or BRAF mutations, and resistance in this setting may be delayed by co-targeting of ERK signalling intermediates. These findings merit broader evaluation in prospective clinical trials.

To address whether Hoip is required for adult hematopoiesis, we used tamoxifen induced Hoip deleted mice ( Hoip fl/fl ; Rosa26-CreERT )...Thus, our data demonstrated that Hoip is essential for adult hematopoiesis and myeloid leukemia. Given that patients with myeloid leukemia have shown increased activity of NF-κB signaling, inhibition of LUBAC ligase activity could serve as a promising strategy for treating myeloid leukemia.

The mechanisms of ALK TKI resistance were heterogeneous; ALK mutations were found in less than one-third of patients. Compound ALK mutations, which may confer lorlatinib resistance, may occur in crizotinib, ceritinib, and alectinib-resistant lung cancers.

Combining cytology with ddPCR analysis of TERT, BRAF and RAS mutations can improve the diagnostic accuracy of thyroid FNABs.

P1/2, N=6, Suspended, National Cancer Institute (NCI) | Active, not recruiting --> Suspended

P1/2, N=6, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting | N=110 --> 6

We first showed the frequency of RAS/RAF mutations in Korean patients with PCM. Screening of these mutations could be considered as a routine clinical test at the time of diagnosis and follow-up due to their influence on clinical outcome, as well as its potential as a therapeutic target.

P1/2, N=30, Recruiting, Guo ShiWei | Not yet recruiting --> Recruiting | Initiation date: Dec 2019 --> Mar 2020