Of various human epidermal growth factor receptor (HER) inhibitors, only the anti-HER2 monoclonal antibody (mAb) Herceptin/trastuzumab and the antibody-drug conjugate trastuzumab deruxtecan (T-Dxd) has been approved for the treatment of patients with stomach cancer...Of various HER inhibitors, the irreversible pan-HER family inhibitors (e.g., afatinib) were more effective than the reversible dual epidermal growth factor receptor (EGFR)/HER2 tyrosine kinase inhibitor (TKI) lapatinib and the EGFR-specific TKI erlotinib in inhibiting the growth of HSCCLs. Of agents targeting different downstream cell signaling molecules, dasatinib targeting Ab1/Src/C-Kit, trametinib targeting MERK1/2 and miransertib targeting AKT1/2/3 inhibited growth of majority of HSCCLs, with the IC50 values ranging from 2 nM to 7 µM...Treatment with neratinib, afatinib, dinaciclib, dasatinib, stattic, miransertib and paclitaxel significantly inhibited migration of stomach cancer cells. Interestingly, treatment with a combination of afatinib and dasatinib or afatinib and miransertib resulted in synergistic and additive growth inhibition of stomach cancer cells. These results suggest that treatment with a combination of these agents may be of therapeutic value in stomach cancer and warrants further investigations.

P2, N=141, Active, not recruiting, Laekna Limited | Trial completion date: Nov 2024 --> Jun 2024

P1, N=21, Completed, Laekna Limited | Recruiting --> Completed

Applying the ML approach to predict the drug response for each medication revealed an upstanding performance for SVM in predicting Afuresertib drug response (area under the curve [AUC] 0.875) using CIT, GAS2L3, STAG3L3, ATP2B4-mut, and IL15RA-mut as molecular features. Furthermore, the ANN algorithm using 9 mRNA characteristics demonstrated the highest prediction performance (AUC 0.780) in Gefitinib with CCL23-mut. This work extensively investigated the mRNA and mutation signatures associated with drug response in LUAD using a machine-learning approach and proposed a priority algorithm to predict drug response for different drugs.

Re-sensitization to cisplatin-induced cell death was achieved using clinically approved compounds aiming to restore p53 wild-type function (PRIMA1-Met), or inhibition of AKT-driven MAPK survival pathways (afuresertib), in both cases being partially due to ferroptosis induction. Consequently, active ferroptosis induction using the GPX4 inhibitor RSL3 proved superior in tumorselectively fighting MM cells. Due to high prevalence of the E285-cluster mutations in MM as well as in a variety of other tumor types, we conclude this cluster to serve an important function in tumor development and therapy and suggest new implications for ferroptosis induction in therapeutic applications fighting MM in particular and cancer in general.

P2, N=141, Active, not recruiting, Laekna Limited | Trial completion date: Sep 2023 --> Nov 2024

Conclusions The preliminary data from the combination therapy of afuresertib plus fulvestrant has shown promising efficacy with a well-tolerated safety profile in patients with HR+/HER2- LA/mBC who progressed on 1-2 prior lines of standard of care therapies. These results support further evaluation of this combination therapy in this patient population in an upcoming phase III study.

Treatment of HUVEC-vPK cells with a pan-AKT inhibitor Miransertib (ARQ 092) reduced the overall phosphorylation of AKT, resulting in the cleavage of Caspase-3 and the induction of apoptosis. vPK expression also inhibited the cytotoxicity of cisplatin in vitro and in vivo. Collectively, our findings demonstrate that vPK's ability to augment cell survival and promote angiogenesis is critically dependent on AKT signaling, which is relevant for future therapies for treating KSHV-associated cancers.

Vevorisertib alone or with paclitaxel or fulvestrant had a manageable safety profile, and vevorisertib alone or with paclitaxel had minimal to modest antitumor activity in this patient population with PIK3CA/AKT/PTEN-mutated advanced solid tumors.

Capivasertib demonstrated single-agent activity and a manageable safety profile in pts with heavily pretreated R/R FL. Notably, no immune-mediated events and no treatment-related deaths were observed. Capivasertib has the potential to be an alternative therapeutic option for pts with R/R B-NHL, with a non-overlapping safety profile compared to currently available PI3Ki.

Among these, the PIK3CA isoform-specific inhibitor alpelisib and the pan-AKT inhibitor capivasertib were recently approved in combination with the estrogen receptor degrader fulvestrant for the treatment of ER+ advanced breast cancer after progression on an aromatase inhibitor. Here, we review the role of the PI3K/AKT/mTOR pathway in ER+ advanced breast cancer, highlighting the genomic contexts in which the various inhibitors of this pathway may have superior activity. We also discuss selected trials with agents targeting the PI3K/AKT/mTOR and related pathways as well as the rationale supporting the clinical development of triple combination therapy targeting ER, CDK4/6 and PI3K/AKT/mTOR in ER+ advanced breast cancer.

The TMZ-resistant T98G cell line as compared to the TMZ-sensitive LN229 cell line shows a high sensitivity towards Ouabain. We consider it as a promising new compound especially in recurrent GBM to overcome the resistance to TMZ and irradiation.

Furthermore, IPAT in combination with carboplatin significantly reduced cell adhesion and inhibited cell invasion. These findings suggest that the combination of IPAT and carboplatin has potential clinical implications for developing new USC treatment strategies.

Capivasertib + fulvestrant significantly improved PFS compared to fulvestrant alone in the overall population, and in patients with AKT pathway-altered tumors, and may become a future treatment option in this setting. The safety profile of capivasertib + fulvestrant was generally manageable and consistent with prior data.

The selective pan-AKT inhibitor, MK-2206, or the microRNA-199a-3p were tested in combination with palbociclib in HCC cell lines and in the TG221 HCC transgenic mouse model. At the molecular level, the combination caused the simultaneous decrease of the phosphorylation of both RB1 and of AKT. Our findings provide pre-clinical evidence for the efficacy of the combination miR-199a-3p/palbociclib as anti-HCC treatment or as a new approach to overcome sorafenib resistance.

Representative experimental validation studies in two breast cancer cell lines showed a reasonable concurrence between the expression data from the RNA-sequencing and qRT-PCR or data from ex vivo inhibition of AKT1 activity in cancer patient-derived cells. In brief, findings presented here provide a resource for further understanding of AKT1-dependent modulation of gene expression in breast cancer cells and broaden the scope and significance of AKT1 targets and their functions.

Phase I/II studies demonstrated greater efficacy when capivasertib was co-administered with paclitaxel, fulvestrant in hormone receptor (HR)-positive, HER2-negative breast cancer or olaparib. Toxicity profile proved to be manageable with hyperglycemia (20-24%), diarrhea (14-17%) and maculopapular rash (11-16%) being the most common grade ≥3 adverse events. Ongoing Phase III trials of capivasertib in combination with fulvestrant (CAPItello-291), CDK4/6 inhibitor palbociclib (CAPItello-292) and paclitaxel (CAPItello- 290) will better clarify the therapeutic role of capivasertib in breast cancer.

Additionally, mice treated with combination therapy also had enrichments in genes sets associated to T cell, NK cell and as well as T cell activation, cytotoxicity, and interferon gamma signature. The findings from this study provide preclinical evidence for the efficacy of combination therapy with abiraterone plus capivasertib and provides insights into its immunomodulatory effects and influence on antitumor immunity.

Using a novel TMA of lobules in combination with DSP, we preliminarily identified immune-based and PI3 kinase-related protein biomarkers in BBD biopsies associated with BC risk. In case-only analyses, these markers demonstrated complex differences between lobules in BBD biopsies, subsequent BCs and adjacent normal lobules.

The activity of vemurafenib and the BRAF V600E-selective inhibitor dabrafenib were not equivalent in this combination screen and greater than additive cytotoxicity was observed more frequently when TAK-243 was combined with vemurafenib than with dabrafenib...Other notable agents combined with ipatasertib included the MEK inhibitors trametinib and selumetinib, both of which produced greater than additive cytotoxicity in spheroids derived from pancreatic cancer metastases...This project was funded in part with federal funds from the NCI, NIH, under contract no. HHSN261201500003I.

This study highlights the utility of NanoString digital profiling methods in RMS, where it can detect distinct molecular signatures with the expression of signaling pathways and microRNAs from FFPE tumor tissue that may help identify prognostic biomarkers of interest. The overexpression of INPP4B and miR-3144-3p, miR-612, miR-302d-3p, miR-421, miR-548y and miR-548ar-5p may be associated with worse overall survival in ERMS and SRMS.

In the established tumor xenograft model, PRDM5 regulated ESCC tumor growth as well as the expression of 14-3-3zeta and phosphorylation of Akt protein. In conclusion, PRDM5 suppresses ESCC cell proliferation and migration and negatively regulates 14-3-3zeta/Akt signaling pathway in vitro and in vivo.

Different doses (0.3μM and 1μM) of the pan-AKT inhibitor (AKTi) ipatasertib were added to the culture during ex vivo expansion...Legal entity responsible for the study Iovance Biotherapeutics, Inc. Funding Iovance Biotherapeutics, Inc.

These results suggest combining T-DXd with capivasertib has potential to be active in breast cancer patients, with activity likely to be enriched in tumours with mutations in PIK3CA and PTEN, but also in tumours with no PI3K pathway activating mutations.

E-cadherin-induced activation of Akt1/2 isoforms was the essential mechanism of chemoresistance, whereas Akt3 made cells more fragile. These findings emphasized the need to target Akt1/2, rather than pan-Akt, as a rational therapeutic approach.

Molecular signatures of increased T cell activity, proliferation, and hormone dependence were associated with greater probability of response to apalutamide in non-metastatic CRPC. Loss of PTEN could be a target for ipatasertib (a pan-AKT inhibitor) associated with abiraterone in mCRPC patients. The 2021 ASCO Genitourinary Cancers Symposium significantly contributed to the complex research goal of intimately understanding PC carcinogenesis with the ultimate aim of improving patient outcomes.

Upregulation of signal transducer and activator of transcription 3 (STAT3) and proviral insertion in murine-1 (PIM-1) were associated with combined apalutamide/GSK690693. Our findings show that apalutamide can attenuate Pten-deficient PCa in a context-specific manner and provides data that can be used to further study and, possibly, develop additional combinations with apalutamide.

Treatment with pan-AKT inhibitor capivasertib in PeCa cell lines induced a significant downregulation of both total AKT and pAKT as well as decreased cell viability and chemotaxis. Selected protein candidates of the mTOR/AKT signaling pathway demonstrate association with histological and survival parameters of PeCa patients, whereas AKT appears to be the most promising one.

We tested the panAKT inhibitor MK-2206, mTOR (Rapamycin), PKC (Enzastaurin), RAF (Sorafenib) and ERK (PD98,059). Conclusion A promising direction for further research in AML and MDS is not only blockage of TIM3 signaling by monoclonal antibodies, but also elucidation of pathways leading to TIM3 expression on malignant cells. Further research is required to identify the mechanisms of Akt-mediated TIM3 downregulation.

Functional assessment of BCL-2 inhibition via Bax translocation assay revealed slightly increased pro-apoptotic signaling after combined MK-2206 and venetoclax incubation. In summary, we demonstrate that the pan-AKT inhibitor MK-2206 potently blocks B-ALL cell proliferation and for the first time characterize the synergistic effect of combined MK-2206 and venetoclax treatment in B-ALL.

P1b, N=77, Terminated, ArQule, Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.) | Completed --> Terminated; Business Reasons

P1b, N=77, Completed, ArQule, Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.) | Active, not recruiting --> Completed | Trial primary completion date: Dec 2020 --> Mar 2021

Our data show evidence of T cells with natural TSON expression. However, additional studies are needed to further understand the role of TSON in immunotherapy.

The results of the IPATential150 phase 3 study (NCT03072238) demonstrated that another oral AKT inhibitor, ipatasertib, prolonged radiographic progression-free survival (rPFS) when combined with abiraterone compared with placebo plus abiraterone in metastatic castration-resistant prostate cancer, particularly among patients with PTEN loss. Secondary endpoints include overall survival, time to start of first subsequent therapy or death, symptomatic skeletal event-free survival, time to pain progression and safety profile. Enrolment started in July 2020.

Clinically meaningful activity with single-agent capivasertib was demonstrated in refractory malignant neoplasms, including rare cancers. ClinicalTrials.gov Identifier: NCT00700882.

Background: Somatic genomic alterations that activate the phosphatidylinositol-3-kinase (PI3K) pathway signaling are found in 30-50% of breast cancers, and the p110a-specific inhibitor alpelisib is approved for use in combination with fulvestrant in PIK3CA mutated hormone receptor-positive (HR+) metastatic breast cancer. We report here the feasibility of quantitative and longitudinal detection of activated AKT in EpCAM/Trop2 captured CTCs from metastatic breast cancer with somatic PIK3CA mutations. Future work will prospectively evaluate multiple clinical applications of this assay in patients receiving alpelisib plus endocrine therapy for PIK3CA mutated HR+ metastatic breast cancer, as well as expanding the assay to include the detection of additional phospho-protein readouts of PI3K pathway activity in CTCs. In addition to the potential to complement solid biopsy PIK3CA mutation status as a predictive biomarker of sensitivity to PI3K therapies, this assay has the unique potential to provide a pharmacodynamic assessment of PI3K inhibitor activity in CTCs while on treatment, which may serve as an early biomarker of clinical response or resistance.

P1b, N=41, Terminated, ArQule | Completed --> Terminated

The pan-AKT inhibitor MK demonstrates significant anti-leukemic potential in BCP-ALL cells of different genetic background. Encouraging effects on MLLr primary cells in the presence of a protecting stroma microenvironment are promising and demand further in vivo Investigation.

The pan-AKT inhibitor MK demonstrates significant anti-leukemic potential in BCP-ALL cells of different genetic background. Encouraging effects on MLLr primary cells in the presence of a protecting stroma microenvironment are promising and demand further in vivo Investigation.