- |||||||||| Preclinical, Journal: Effect of Panax ginseng and Fructus Mume on Intestinal Barrier and Gut Microbiota in Rats with Diarrhea. (Pubmed Central) - Mar 20, 2023
Furthermore, RW suppressed levels of interleukin (IL), tumor necrosis factor (TNF)-?, IL-1, PI3K, Akt, and p-NF-?B p65 and also increased IL-4 levels. Our study indicates that P. ginseng and Fructus mume help improve the symptoms of diarrhea, possibly by alleviating the intestinal barrier injury, regulating intestinal flora composition, and inhibiting the PI3K/Akt/NF-?B signaling pathway.
- |||||||||| Journal: TMAO promotes dementia progression by mediating the PI3K/Akt/mTOR pathway. (Pubmed Central) - Mar 20, 2023
Our study indicates that P. ginseng and Fructus mume help improve the symptoms of diarrhea, possibly by alleviating the intestinal barrier injury, regulating intestinal flora composition, and inhibiting the PI3K/Akt/NF-?B signaling pathway. This study determined that TMAO promotes dementia through the PI3K/Akt/mTOR signaling pathway, suggesting that TMAO may be a potential target for dementia.
- |||||||||| Piqray (alpelisib) / Novartis, capivasertib (AZD5363) / Otsuka, AstraZeneca
Review, Journal: Drugging the PI3K/AKT/mTOR Pathway in ER+ Breast Cancer. (Pubmed Central) - Mar 16, 2023
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.
- |||||||||| Itari (linperlisib) / Shanghai YingLi Pharma
Enrollment open: Efficacy and Safety of PI3K Inhibitors in Relapsed/Refractory Large Granular T Lymphocytic Leukemia (clinicaltrials.gov) - Mar 16, 2023
P1, N=8, Recruiting,
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. Not yet recruiting --> Recruiting
- |||||||||| LY294002 / Eli Lilly
Journal: Ginkgolide B caused the activation of the Akt/eNOS pathway through the antioxidant effect of SOD1 in the diabetic aorta. (Pubmed Central) - Mar 15, 2023
The relaxation by GB was abolished by prior incubation with L-NNA (an endothelial nitric oxide synthase (NOS) inhibitor), LY294002 (a phosphoinositide 3-kinase (PI3K) inhibitor), and Akt inhibitor, confirming the essential role of PI3K/Akt/eNOS signaling pathway...The superoxide dismutase1 (SOD1) expression level decreased in DM aortas, but GB stimulation increased SOD activity and SOD1 expression in DM aortas. Our novel findings suggest that in DM aortas, endothelial-dependent relaxation induced by GB was mediated by activation of SOD1, resulting in activation of the Akt/eNOS signaling pathway.
- |||||||||| Piqray (alpelisib) / Novartis
Journal: Alpelisib Efficacy Without Cherry-PI3King Mutations. (Pubmed Central) - Mar 15, 2023
However, 20% of PIK3CA mutations occur in non-hotspot regions. A recent article demonstrated that patients with cancers bearing non-hotspot PIK3CA mutations also derived benefit from alpelisib, which will inform clinical decision-making moving forward.
- |||||||||| Journal, Tumor mutational burden, Heterogeneity: Genetic heterogeneity and tissue-specific patterns of tumors with multiple PIK3CA mutations. (Pubmed Central) - Mar 15, 2023
A recent article demonstrated that patients with cancers bearing non-hotspot PIK3CA mutations also derived benefit from alpelisib, which will inform clinical decision-making moving forward. Our pan-tumor study provides biological insights into the genetic heterogeneity and tissue specificities of multi-PIK3CA mutations, with potential clinical utility to guide PI3K inhibition strategies.
- |||||||||| Piqray (alpelisib) / Novartis
Review, Journal: The emerging role of PI3K inhibitors for solid tumour treatment and beyond. (Pubmed Central) - Mar 15, 2023
Although several PI3K inhibitors are approved for haematological malignancies, only alpelisib was approved in solid tumours and for the treatment of PIK3CA-related overgrowth spectrum (PROS) syndrome...While extreme selectivity can be hypothesised to grant activity and safety advantage to these novel agents, on the other hand reduced benefit can be speculated for patients harbouring multiple or rare PIK3CA mutations. This review summarises the current understanding of PI3K alterations and the state-of-the-art treatment strategies in PI3K driven solid tumours, while also exploring the potential intrinsic and acquired resistance mechanisms to these agents, and the emerging role of mutant selective PIK3CA inhibitors.
- |||||||||| Lorbrena (lorlatinib) / Pfizer, RSL3 / Stanford University
Journal: Inhibiting SCD expression by IGF1R during lorlatinib therapy sensitizes melanoma to ferroptosis. (Pubmed Central) - Mar 14, 2023
Finally, lorlatinib treatment sensitized melanoma to GPX4 inhibition in preclinical animal models, and melanoma patients with low GPX4 and IGF1R expression in their tumors survived for longer period. Altogether, lorlatinib sensitizes melanoma to ferroptosis by targeting IGF1R-mediated PI3K/AKT/mTOR signaling axis, suggesting that combination with lorlatinib could greatly expand the utility of GPX4 inhibition to melanoma patients with IGF1R-proficient expression.
- |||||||||| pioglitazone / Generic mfg.
Journal: Synergistic effects of PI3K inhibition and pioglitazone against acute promyelocytic leukemia cells. (Pubmed Central) - Mar 14, 2023
The EMT-CTC axis could be targeted for preventive measures during MORA treatment to inhibit the associated tumor metastasis or recurrence in BC patients. This study sheds light on the significance of the PI3K/Akt pathway in APL cell sensitivity to pioglitazone and proposed that the presence of the PI3K inhibitor in the therapeutic regimen containing pioglitazone could be promising in the treatment of this malignancy.
- |||||||||| mTOR regulates stem cells of glioblastoma by altering the self-renewal and proliferation (Section 1; Poster Board #17) - Mar 14, 2023 - Abstract #AACR2023AACR_8792;
GBM stem cells were treated with various inhibitors of canonical PI3K/AKT/mTOR pathways such as rapamycin (mTORC1 inhibitor), PP242 (ATP binding mTORC1/2 inhibitor), LY294002 (PI3K inhibitor), and MAPK inhibitor, U0126...Treatment with novel small molecule dual inhibitors of mTORC1/2 demonstrated that Torin1 and Torin2 suppressed the proliferation of GBM CSC, while XL388 was less effective...Additionally, Torin2 was able to eradicate tumor cells. Torin2 effectively targeted CSCs of GBM by halting self-renewal and inhibiting cell proliferation, underscoring the use of Torin2 in the treatment of GBM.
- |||||||||| PIK-75 / VetDC
Discovery of mechanisms that modulate the hippo pathway and CDK6 expression in CDK4/6 inhibitor resistant breast cancer cells (Section 9; Poster Board #4) - Mar 14, 2023 - Abstract #AACR2023AACR_8571;
The current standard of care in advanced HR+ breast cancer includes endocrine therapy (tamoxifen, aromatase inhibitors, etc) and CDK4/6 inhibitors...We discovered staurosporine and the PI3K inhibitor PIK-75 as small molecules that potently downregulate CDK6 expression in breast cancer cells...By kinase profiling combined with a small hairpin RNA (shRNA) screen, we discovered the mechanisms that resulted in CDK6 downregulation and modulation of the hippo pathway to reverse the CDK4/6 inhibitor resistance. Our discovery has implications for therapeutic development in this group of patients posing a huge unmet need.
- |||||||||| Kisqali (ribociclib) / Novartis, Stivarga (regorafenib) / Bayer, Aliqopa (copanlisib) / Bayer
Identifying novel combination therapies for Ewing sarcoma (Section 41; Poster Board #20) - Mar 14, 2023 - Abstract #AACR2023AACR_8254;
We demonstrated that the combination of ribociclib, a CDK 4/6 inhibitor, and regorafenib, a VEGFR inhibitor, exhibited additivity and synergy in Ewing cell lines...Similarly, cell lines treated with copanlisib, a PI3K inhibitor, and ribociclib, two FDA-approved drugs, synergistically inhibited cell line viability in vitro and impaired xenograft proliferation in vivo...This work demonstrates that CDK 4/6 inhibitors show synergistic activity with both VEGFR inhibitors and PI3K inhibitors in Ewing Sarcoma by impairing the growth of cultured Ewing cells and improving the survival of mice with Ewing sarcoma. We believe that pre-clinical validation of novel approved drug combinations in Ewing sarcoma will accelerate the development of early phase trials for patients with relapsed refractory disease, a group of patients greatly in need of new therapeutic opportunities.
- |||||||||| PI-103 / Roche
Overcoming roadblocks of immunotherapy in non-small cell lung cancer (Section 22; Poster Board #11) - Mar 14, 2023 - Abstract #AACR2023AACR_7445;
Here, we introduce antibody conjugated drug loaded nanotherapeutics (ADNs) consisting of a targeted therapy drug, phosphatidylinositol 3-kinase (PI3K) inhibitor PI103, and decorated with two ICIs for CD47 and PDL1...Reduced tumor growth and higher survival probability have been observed in the syngeneic LLC tumor model for anti-CD47-PDL1-ADN than monotherapy and traditional immunotherapy.In summary, we have introduced a lung cancer treatment strategy that can be an effective therapy for NSCLC patients, irrespective of the PDL1 expression level. The strategy combining bispecific immunotherapy and targeted therapy for activating the innate and adaptive immune systems and delivering targeted therapy drugs can emerge as a significant advance in the treatment of NSCLC patients.
- |||||||||| Piqray (alpelisib) / Novartis
Identification of novel regulators of response to PI3Ka inhibition in PIK3CA mutant gastric cancer (Section 15; Poster Board #27) - Mar 14, 2023 - Abstract #AACR2023AACR_7350;
These data suggest that while CBFB loss is a key step in the development of PI3K? inhibitor resistance, PIK3CA mutant gastric tumors may be good candidates for clinical success with BYL719 alone and resistance could be prevented with combination with a PIM kinase inhibitor.
- |||||||||| Copiktra (duvelisib) / Secura Bio, Yakult Honsha
Duvelisib eliminates CLL B Cells, impairs CLL-supporting cells, and overcomes ibrutinib resistance in a patient-derived xenograft model (Section 15; Poster Board #11) - Mar 14, 2023 - Abstract #AACR2023AACR_7334;
In support of this, we identified an ibrutinib resistant CLL patient, with a clone exhibiting BTK and PLC?2 mutations who responded immediately to single agent duvelisib with redistribution lymphocytosis followed by a partial clinical remission associated with subsequent modulation of T and myeloid cells.In conclusion, our data define the mechanism of action whereby dual inhibition of PI3K-?,? affects CLL B cell numbers and T and myeloid cell pro-leukemia functions, supporting the use of duvelisib as a potentially valuable therapeutic intervention, including for patients refractory to BTKi.
- |||||||||| MK-2206 / Merck (MSD), perifosine (D21266) / AEterna Zentaris, AT13148 / Otsuka
Targeted investigational oncology agents (IOA) in the NCI60: a phenotypic systems-based resource (Section 13; Poster Board #27) - Mar 14, 2023 - Abstract #AACR2023AACR_7230;
The AKT cluster includes both allosteric (MK-2206) and competitive inhibitors highlighting the NCI60 is a functional cell assay...The mTOR inhibitors (12/20) form a connected cluster at 0.7 COMPARE correlation, with half of the non-connected mTOR singletons representative of the rapamycin class of inhibitors...NCI60 compound suppliers can incorporate their test compound(s) data to use the interactive visualization tools with AOD and IOA agents. This project was funded in part with federal funds from the NCI, NIH, under Contract # 75N91019D00024/75N91020F00003.
- |||||||||| Piqray (alpelisib) / Novartis
PI3K inhibition sensitize cancer cells to tumor treating fields (TTFields) (Section 13; Poster Board #3) - Mar 14, 2023 - Abstract #AACR2023AACR_7207;
Further studies will expand on the mechanism of this combination therapy. The current study demonstrates that the PI3K/AKT signaling pathway is involved in reduced cancer cell sensitivity to TTFields, and that PI3K inhibition can further sensitize cancer cells to TTFields.
- |||||||||| Synergy between FAK and PI3K inhibitors in cervical and pancreatic cancer cells (Section 38; Poster Board #5) - Mar 14, 2023 - Abstract #AACR2023AACR_7071;
Interestingly, PI3K inhibitors induced activation of several RTK including insulin R and IGF-1R in cervical cancer cells, as well as EGFR, Her2, Her3, Axl, and EphA2 in pancreatic cancer cells. Together, our results show the promise of combining FAK and PI3K inhibition for cervical cancer and pancreatic cancer treatment, but biomarkers for sensitivity to the combination are needed, and concomitant RTK inhibition may be required to combat potential resistance to the combination.
- |||||||||| tumor adaptations to PI3K inhibition increases and its reversibility decreases as a function of time in drug (Section 16; Poster Board #1) - Mar 14, 2023 - Abstract #AACR2023AACR_6106;
The data suggests that induction of adaptive resistance is in part responsible for the continued persistence of tumor masses after the initial response to targeted therapy but also selectively sensitizes them towards Mcl1/Bcl2 inhibitors due to the upregulation of an anti-apoptotic program. Therefore, pulsatile targeted inhibition of PI3K in combination with anti-apoptotic BH3 domain protein inhibitors in a subset of breast cancer patients may provide a wide therapeutic window and can circumvent chronic adaptation induced resistance and drive potent cell death thereby improving therapeutic outcomes.
- |||||||||| Piqray (alpelisib) / Novartis, Mekinist (trametinib) / Novartis
Effective anti-tumor effect in a rare metastatic Wilms tumor xenograft by inhibition of RAS/PI3K hyperactivation (Section 42; Poster Board #12) - Mar 14, 2023 - Abstract #AACR2023AACR_5929;
While efficacy data generated in PDX derived from patients is not used to guide clinical decisions at this time, it can validate therapeutic approaches and provide rationale for future clinical trials. In conclusion, these studies provide critical feasibility data that has high translational value and great potential to improve survival and quality of life for children suffering with progressive WT.
- |||||||||| Treatment of PTEN/PI3K co-mutated endometrial adenocarcinoma with multitarget small molecule inhibitors (Section 42; Poster Board #5) - Mar 14, 2023 - Abstract #AACR2023AACR_5922;
Dual-target inhibitors LCI133 and LCI136 are nanomolar potent in AN3-CA and RL95-2 EC cell lines, suggesting a role of CDK9 inhibition of PTEN/PI3K co-mutated EC. Preliminary studies demonstrate an upregulation of MYC gene and protein expression in FBXW7mut EC but not FBXW7wt, and the role of FBXW7 as a predictive biomarker in treatment of PTEN/PIK3R1 co-mutated EC warrants further investigation.
- |||||||||| Piqray (alpelisib) / Novartis, GSK2636771 / GSK
Targeting PI3K isoforms to improve the effectiveness of T cell mediated immunotherapy (Section 40; Poster Board #30) - Mar 14, 2023 - Abstract #AACR2023AACR_5880;
inhibitor can potentiate T cell-mediated antitumor immune responses regardless of PTEN status, providing a strong rationale for the clinical development of the BYL-based IO combination. In collaboration with Novartis, MD Anderson Cancer Center will launch a Phase I/II trial of the FDA-approved BYL in combination with ?PD1 in advanced melanoma and breast cancer patients.
- |||||||||| A genetic-metabolic circuit of liver-specific metastatic organotropism (Room W311 A-D - Convention Center) - Mar 14, 2023 - Abstract #AACR2023AACR_5657;
Lastly, analysis of 243 human liver vs extra-hepatic metastases across 75 cancers and addition of newly generated RNA-seq data of additional melanoma LM, revealed concordant pathways enrichment of glycolysis and oxidative phosphorylation LM. Together, we identify an axis of liver-metastatic organotropism that can be abrogated with a combination of PI3K inhibition and SGLT2-inhibition or concurrent ketogenic diet.
- |||||||||| Piqray (alpelisib) / Novartis
NOS inhibition reverses epithelial-to-mesenchymal transition and synergizes with alpelisib in metaplastic breast cancer (Room W331 - Convention Center) - Mar 14, 2023 - Abstract #AACR2023AACR_5571;
P1/2
The clinical benefit rate was 40% (6/15), overall response rate was 20% (3/15), and one patient achieved a pathologic complete response. Relative to baseline tumors, the responder end-of-treatment tumors had undergone reversal of EMT, with decreased expression of iNOS and ALDH1.We find that combining L-NMMA and alpelisib is a novel therapeutic strategy to treat MpBC, and combination therapy is being tested in a first multicenter phase 2 study for patients with MpBC.
- |||||||||| Piqray (alpelisib) / Novartis, LY294002 / Eli Lilly
The role of the PI3K/Akt signaling pathway on LIN28B-mediated colorectal cancer metastasis (Section 5; Poster Board #24) - Mar 14, 2023 - Abstract #AACR2023AACR_5375;
Immunohistochemical staining revealed that Alpelisib did not affect proliferation, apoptosis, or angiogenesis of the liver metastases, whereas DAPT may inhibit angiogenesis.Taken together, our results indicate that LIN28B promotes cell migration and liver metastasis formation through CLDN1 and NOTCH3-mediated activation of PI3K signaling. Development of new therapies that target the PI3K/Akt pathway may provide an effective strategy for preventing metastases in CRC patients.
- |||||||||| LY294002 / Eli Lilly
Loss of AKT2 correlates with activation of ?-catenin signaling in immortalized mouse hepatocytes (Section 8; Poster Board #15) - Mar 14, 2023 - Abstract #AACR2023AACR_5221;
These changes correlated with increased expression of AKT1 and total phosphorylated AKT in the Pten; Akt2 DM group. These findings suggest the need to further evaluate the role of AKT isoforms in the PI3K/AKT/?-catenin signaling axis and a promise for evaluation of isoform-specific inhibitors targeted at AKT to block tumor growth.
- |||||||||| 5-fluorouracil / Generic mfg.
Targeting PI3Kinase AKT pathway and anti-apoptotic protein XIAP in chemotherapy-resistant colorectal cancer cells (Section 8; Poster Board #5) - Mar 14, 2023 - Abstract #AACR2023AACR_5211;
Following treatment with LY294002 or Embelin alone or in combination for 48hrs, HCT-116OXR cells underwent a G1 phase cell cycle arrest rather than apoptosis as measured by flow cytometry analysis. The data suggests that PI3K/AKT pathway and XIAP inhibitors cause cell cycle arrest and decreased cell viability in oxaliplatin resistant colorectal cancer cells, which may have implications for treatment of chemotherapy resistant CRC.
- |||||||||| MEN1611 / Menarini, Orserdu (elacestrant) / Menarini
The oral SERD Elacestrant in combination with the PI3K inhibitor MEN1611 inhibits tumor growth in ER+/HER2- breast cancer in vitro and in PDX models (Section 20; Poster Board #7) - Mar 14, 2023 - Abstract #AACR2023AACR_4978;
Overall, in all the tested in vivo models the combination of Elacestrant and MEN1611 was superior in comparison to the single agents by overcoming resistance to ER inhibition potentially driven by PI3K pathway activation in PIK3CA mutated tumors. The current data support the use of Elacestrant, the first oral SERD with positive phase III results in the EMERALD trial (Bidard et al.; JCO 2022), in combination with the PI3K inhibitor MEN1611, in ER+/HER2- mBC patients harboring PIK3CA mutations and who progressed to CDK4/6i plus ET.
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