- |||||||||| Comprehensive Drug Profiling and CRISPR Screening Reveal Essential Pathways for NK Cell Cytotoxicity (Marriott Grand Ballroom 8-9 (Marriott Marquis San Diego Marina)) - Nov 6, 2024 - Abstract #ASH2024ASH_1631;
In addition, pevonedistat, daporinad, and bryostatin 1 enhanced NK cell activity, whereas sotrastaurin showed strong NK cell-inhibiting effects...Various NAMPT inhibitors (KPT-9274, GMX1778 and LSN3154567) not included in the original screens showed similar effects to daporinad in AML and ALL cell lines...In conclusion, our study identifies PKC, NAMPT, and NEDD8 having an essential role in controlling NK cell-mediated killing and suggests potential compounds to enhance NK cell effectiveness in treating hematological malignancies. These findings offer insights into developing combination immunotherapy strategies to improve treatment outcomes.
- |||||||||| padnarsertib (KPT-9274) / Karyopharm
Journal: Inhibition of NAMPT by PAK4 Inhibitors. (Pubmed Central) - Sep 29, 2024
KPT-9274, a PAK4 inhibitor, significantly reduces the growth of triple-negative breast cancer cells and mammary tumors in mouse models, and it also inhibits the growth of several other types of cancer cells...Molecular docking studies were also used to help us better understand the mechanism by which PAK4 inhibitors block PAK4 and NAMPT activity, and we identified specific residues on the PAK4 inhibitors that interact with NAMPT and PAK4. Our results suggest that PAK4 inhibitors may have a more complex mechanism of action than previously understood, necessitating further exploration of how they influence cancer cell growth.
- |||||||||| padnarsertib (KPT-9274) / Karyopharm
Journal: Dual-inhibition of NAMPT and PAK4 induces anti-tumor effects in 3D-spheroids model of platinum-resistant ovarian cancer. (Pubmed Central) - May 17, 2024
Moreover, the compound reduced PAK4 activity by altering its mostly cytoplasmic localization, leading to NAD+-dependent decreases in phosphorylation of S6 Ribosomal protein, AKT, and ?-Catenin in the cytoplasm. These findings suggest that KPT-9274 could be a promising treatment for ovarian cancer patients who are resistant to platinum drugs, emphasizing the need for precision medicine to identify the specific NAD+ producing pathway that a tumor relies upon before treatment.
- |||||||||| padnarsertib (KPT-9274) / Karyopharm
Enrollment change, Trial termination, Metastases: TEACH: A Study of Evaluating Dual Inhibitor of PAK4 and NAMPT ATG-019 in Advanced Solid Tumors or Non-Hodgkin's Lymphoma (clinicaltrials.gov) - Apr 29, 2024
P1, N=20, Terminated,
These findings suggest that KPT-9274 could be a promising treatment for ovarian cancer patients who are resistant to platinum drugs, emphasizing the need for precision medicine to identify the specific NAD+ producing pathway that a tumor relies upon before treatment. N=70 --> 20 | Recruiting --> Terminated; Because the sponsor modified the study-product development strategy.
- |||||||||| padnarsertib (KPT-9274) / Karyopharm
Preclinical, Journal: Targeting NAD+ metabolism: Pre-clinical insights into potential cancer therapy strategies. (Pubmed Central) - Apr 15, 2024
NAMPT inhibition (alone or in combination with other cancer therapies, including endocrine therapy and chemotherapy) results in decreased cell viability and tumor burden for many cancer types. Many NAMPT inhibitors (NAMPTi) tested before were discontinued due to toxicity; however, a novel NAMPTi, KPT-9274, is a promising, low-toxicity option currently in clinical trials.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, padnarsertib (KPT-9274) / Karyopharm
Journal, IO biomarker: Monosomy 7/del(7q) Cause Sensitivity to Inhibitors of Nicotinamide Phosphoribosyltransferase in Acute Myeloid Leukemia. (Pubmed Central) - Jan 10, 2024
Furthermore, the combination of the BCL2 inhibitor venetoclax and the NAMPT inhibitor KPT-9274 resulted in the death of significantly more leukemic blasts in AML samples with -7/-7q compared to the NAMPT inhibitor alone. In conclusion, our findings demonstrate that AML with -7/-7q are highly sensitive to NAMPT inhibition, suggesting that NAMPT inhibitors have the potential to be an effective targeted therapy for patients with monosomy 7 or del(7q).
- |||||||||| Computational Discovery and Validation of NAD+ Biosynthesis As Unique Vulnerability in B-Lymphoid Malignancies (Grand Hyatt - Grand Hall B) - Nov 3, 2023 - Abstract #ASH2023ASH_3030;
P1
Likewise, inhibitors of B-cell signaling (e.g. ibrutinib) and selective depletion of B-cells (e.g. rituximab, CD19 CAR-T cells) have achieved important progress and are well tolerated...To verify these results based on the DepMap dataset and our drug discovery tool (lymphoblasts.org), we studied the effects of seven NAMPT inhibitors (CAY10618, FK866, GMX1778, OT82, STF118804, STF31 and KPT9274) on a panel of myeloid leukemia and solid tumor cell lines as well as PDX from patients with B-ALL and mantle cell lymphoma... These findings highlight that the classical
- |||||||||| metformin / Generic mfg.
Metabolism-Related Features Identify the Combination Metformin Plus NAMPT Inhibitors As a Selective Treatment Strategy in Acute Myeloid Leukemia (SDCC - Room 6CF) - Nov 3, 2023 - Abstract #ASH2023ASH_1339;
In contrast, high mtDNAcn was not a predictive survival marker in a cohort of adult AML patients treated with venetoclax (VEN) + hypomethylating agents (HMA), indicating that these metabolic features are specifically linked to the resistance to intensive chemotherapy...Due to the link between mtDNAcn and mt complex I activity, we investigated if the treatment with metformin, known to inhibit complex I, would sensitize AML patients with high mtDNAcn to the standard of care AML drugs, such as Cytarabine (AraC), FLT3-inhibitors and VEN...Concomitantly, OXPHOS and glycolysis were diminished upon KPT-9274+metformin, suggesting that the combination was able to bypass the metabolic rewiring of the AML cells. In conclusion, we uncover a subgroup of patients with high mtDNAcn linked to increased mtOXPHOS that is resistant to chemotherapy-induced apoptosis and is characterized by poor clinical outcomes, which can be overcome by the inhibition of the mt complex I. Moreover, the quantification of mtDNAcn can be easily incorporated into clinical practice as a simple and cost-effective metabolic readout of AML patients to identify metabolic vulnerabilities.
- |||||||||| padnarsertib (KPT-9274) / Karyopharm
Enrollment open: KPT-9274 in Patients With Relapsed and Refractory Acute Myeloid Leukemia (clinicaltrials.gov) - Aug 22, 2023
P1, N=40, Recruiting,
Our findings emphasize the heterogeneity in DLBCL, similarities and differences between canine and human DLBCL, and ultimately identify biomarkers that may help guide the choice of chemoimmunotherapy treatment in dogs. Suspended --> Recruiting
- |||||||||| Ibrance (palbociclib) / Pfizer, padnarsertib (KPT-9274) / Karyopharm
Journal, Metastases: NAD?+?Metabolism Generates a Metabolic Vulnerability in Endocrine-Resistant Metastatic Breast Tumors in Females. (Pubmed Central) - May 12, 2023
We show that NAMPT inhibitor KPT-9274 and fulvestrant (Fulv) works synergistically to reduce metastatic tumor burden...Targeting metabolic adaptations in endocrine-resistant metastatic breast cancer is a novel strategy, and alternative approaches aimed at improving the therapeutic response of metastatic ER+ tumors are needed. Our findings uncover the role of ER?-NAMPT cross-talk in metastatic breast cancer and the utility of NAMPT inhibition and antiestrogen combination therapy in reducing tumor burden and metastasis, potentially leading to new avenues of metastatic breast cancer treatment.
- |||||||||| daporinad (APO866) / Onxeo, padnarsertib (KPT-9274) / Karyopharm, Lynparza (olaparib) / Merck (MSD), AstraZeneca
Sensitivity to NAMPT inhibition: In vitro and in vivo characterization in ovarian cancer (Section 14; Poster Board #26) - Mar 14, 2023 - Abstract #AACR2023AACR_7258;
In addition to a synergistic growth inhibitory response in ovarian cancer cells, preclinical combination studies of NAMPTis with olaparib, an approved PARP inhibitor, exhibited higher levels of DNA damage accumulation than with single drug treatments. Our in vitro and in vivo characterizations of NAMPT inhibition suggest that NAMPTis as either single agents or in combination treatments with PARP inhibitors should be investigated further as potential treatment options for ovarian cancer patient populations.
- |||||||||| adagrasib (MRTX849) / Mirati, padnarsertib (KPT-9274) / Karyopharm, Lumakras (sotorasib) / Amgen
Novel Combination to Enhance the Antitumor Activity of KRASG12C Targeted Drugs (Coastal ABCD) - Nov 7, 2022 - Abstract #APAPancreatic2022APA_Pancreatic_126;
Background : KRASG12C inhibitors sotorasib and adagrasib have shown promising results in preclinical and clinical studies. This is the first study showing that KRASG12C inhibitors can synergize with PAK4 inhibitors resulting in improved antitumor activity.
- |||||||||| Monosomy 7 and Del(7q) Cause Selective Sensitivity to Inhibitors of Nicotinamide Phosphoribosyltransferase in Acute Myeloid Leukemia (ENMCC - Hall E) - Nov 4, 2022 - Abstract #ASH2022ASH_3401;
To further support our findings, we analyzed the sensitivity of AML cells without or with -7/-7q to four NAMPT inhibitors (daporinad, GMX1778, KPT-9274, and LSN3154567) using multiparametric flow cytometry...Interestingly, the analysis of ex vivo drug sensitivities also revealed that while the majority of AML with -7/-7q are resistant to the FDA-approved BCL2 inhibitor venetoclax, they are highly sensitive to daporinad (Figure A)...In conclusion, we have found that AML with NAMPT haploinsufficiency caused by -7/-7q shows selective sensitivity to NAMPT inhibition. This suggests that NAMPT inhibitors have the potential to be a potent targeted therapy for AML with -7/-7q, a disease with a particularly adverse prognosis.
- |||||||||| KPT-9274 / Karyopharm
Review, Journal: Recent advances on development of p21-activated kinase 4 inhibitors as anti-tumor agents. (Pubmed Central) - Sep 20, 2022
Herein, we provide an update on recent research progress on the PAK4 mediated signaling pathway and highlight the development of the PAK4 small molecular inhibitors in recent 5 years. Meanwhile, challenges, limitations, and future developmental directions will be discussed as well.
- |||||||||| CRA-026440 / Quest Diagnostics, KPT-9274 / Karyopharm, REC-2282 / Recursion Pharma
Journal, Epigenetic controller: Targeting DNA damage repair functions of two histone deacetylases, HDAC8 and SIRT6, sensitizes acute myeloid leukemia to NAMPT inhibition. (Pubmed Central) - Mar 15, 2022
Our preclinical results provide a rationale for targeting the NAMPT-dependent alternative NAD biosynthesis pathway as a novel clinical strategy against gliomas. Our findings provide evidence that HDAC8 inhibition- or shSIRT6-induced DNA repair deficiencies are potently synergistic with NAMPT targeting, with minimal toxicity towards normal cells, providing a rationale for a novel-novel combination-based treatment for AML.
- |||||||||| KPT-9274 / Karyopharm, PF-3758309 / Pfizer
PAK4 inhibition improves PD1 blockade immunotherapy in prostate cancer (Section 36) - Mar 9, 2022 - Abstract #AACR2022AACR_6058;
A combination of KPT and αPD1 significantly reduced tumor growth when compared to WT (P<.01) and WT αPD1 (P<.01). In conclusion, PAK4 inhibition increased immune infiltration and improved αPD1 treatment response in preclinical mouse prostate cancer models.
- |||||||||| daporinad (APO866) / Onxeo, KPT-9274 / Karyopharm
Pan-cancer analysis of NAMPT inhibitors reveals unique sensitivities to multiple NAMPT inhibitors in several cancer types (Section 6) - Mar 9, 2022 - Abstract #AACR2022AACR_4928;
Furthermore, the molecular predictors of response identified in our screen may ultimately be useful in developing diagnostic tools for enrollment in biomarker-enriched clinical trials aimed at determining the potential use of NAMPT inhibitors. These results suggest the inhibitors’ therapeutic potential in patient populations presenting with AML, ovarian cancer, Ewing’s sarcoma and SCLC all of which currently have high unmet needs.
- |||||||||| fulvestrant / Generic mfg.
ERα and NAMPT crosstalk at enhancers drives Fulvestrant resistance in metastatic breast tumors (Section 27) - Mar 9, 2022 - Abstract #AACR2022AACR_4634;
Mechanistically, chromatin immunoprecipitation showed that NAMPT is recruited to ERα binding sites in MBC xenografts and PDX tumors. Targeting metabolic adaptations in endocrine-resistant metastatic breast tumors is a novel approach that could lead to new combined therapies that reduce mortality.
- |||||||||| daporinad (APO866) / Onxeo, KPT-9274 / Karyopharm
Repurposing NAD Salvage Inhibitors for GCB Diffuse Large-B Cell Lymphoma (GWCC - B213-B214, Level 2) - Nov 5, 2021 - Abstract #ASH2021ASH_2292;
As a proof of concept, we have demonstrated that Dasatinib, a Src/Abl inhibitor approved for B-cell Acute Lymphoblastic Leukemia and Chronic Myelogenous Leukemia, is highly effective in PTEN-positive DLBCLs, irrespective of their COO class (Scuoppo et al., PNAS 2019)...First, we found that the activities of three chemically distinct drugs (FK-866, STF-118804 and KPT-9274) were highly correlated across the 34 lines DLBCL panel...These results were validated in xenotransplants of luciferized DLBCL lines and Patient Derived Xenotransplant models (PDXs) that were transcriptionally classified for the status of the Kynurenine De Novo signature. Together, these data support the repositioning of NAMPT inhibitors as a therapeutically relevant strategy for EZB-type GCB-DLBCLs.
- |||||||||| daporinad (APO866) / Onxeo, KPT-9274 / Karyopharm
Dual Targeting PAK4 and NAMPT As a Novel Therapeutic Approach for Aggressive Non-Hodgkin’s Lymphoma (GWCC - B213-B214, Level 2) - Nov 5, 2021 - Abstract #ASH2021ASH_2168;
P1
Similar results were obtained with positive controls PAK4 [PF-3578309] and NAMPT specific inhibitors [FK-866]...We then showed KPT-9274 to synergize with the standard of care chemotherapy cyclophosphamide, vincristine, and adriamycin used for NHL management (decreased IC25 and IC50 in several combination treatments)...The anti-tumor potential of KPT-9274 ± niacin in several aggressive lymphoma models strongly supports its efficacy in this setting. It strengthens our phase I study design to evaluate safety and tolerability and anti-tumor activity in patients with advanced solid malignancies or NHL (NCT02702492).
- |||||||||| padnarsertib (KPT-9274) / Karyopharm
Enrollment open, Trial initiation date: KPT-9274 in Patients With Relapsed and Refractory Acute Myeloid Leukemia (clinicaltrials.gov) - Sep 5, 2021
P1, N=40, Recruiting,
We, therefore, put forward a logical argument that kaempferol can be further evaluated as a potential PAK4 inhibitor in TNBC. Not yet recruiting --> Recruiting | Initiation date: Dec 2021 --> Aug 2021
- |||||||||| KPT-9274 / Karyopharm, PF-3758309 / Pfizer, FRAX597 / Afraxis, Roche, Scripps Research Institute
Journal: p21-activated kinases as viable therapeutic targets for the treatment of high-risk Ewing sarcoma. (Pubmed Central) - Jul 30, 2021
In addition, the analysis showed enrichment of anti-tumor immune regulatory mechanisms, including interferon (IFN)-ɣ and IFN-α responses. Altogether, our molecular and pre-clinical studies are the first to establish a critical role for PAKs in ES development and progression, and consequently as viable therapeutic targets for the treatment of high-risk ES in the near future.
- |||||||||| padnarsertib (KPT-9274) / Karyopharm
Enrollment change, Trial termination, Trial primary completion date, Metastases: PAK4 and NAMPT in Patients With Solid Malignancies or NHL (PANAMA) (clinicaltrials.gov) - Jun 25, 2021
P1, N=60, Terminated,
Consistent with this, sequencing analysis of PAK4 overexpressing cells indicate that PAK4 has a role in activation of the mTOR pathway. N=130 --> 60 | Recruiting --> Terminated | Trial primary completion date: Aug 2021 --> Feb 2021; sponsor decision
- |||||||||| KPT-9274 / Karyopharm, Sutent (sunitinib) / Pfizer
[VIRTUAL] Novel targets for therapy resistant pancreatic neuroendocrine tumors () - Mar 11, 2021 - Abstract #AACR2021AACR_3725;
Current therapeutic approaches for advanced PNET patients include chemotherapy (Capecitabine, Temolozomide, 5FU etc), targeted therapies (everolimus, and sunitinib), hormonal therapies [somatostatin analogs (octreotide or lanreotide)] and the novel peptide receptor radionuclide therapy...Importantly, combination treatment of KPT-9274 (150mg/kg) and everolimus (2.5 mg/kg used at sub-optimal dose) caused reduction of PNET xenografts. Our investigations demonstrate that PAK4 and NAMPT are two viable therapeutic targets in the difficult to treat PNETs that warrant further clinical investigations.
- |||||||||| tamoxifen / Generic mfg.
[VIRTUAL] Targeting metabolic vulnerabilities of endocrine resistant breast cancers using XPO1 and NAMPT inhibition () - Mar 11, 2021 - Abstract #AACR2021AACR_2200;
Targeting drug and metastatic-site induced adaptations to regenerate new vulnerabilities in endocrine-resistant breast tumors are novel. Given the need for better strategies for improving therapy response of metastatic ER+ tumors, our findings show uncovering the role XPO1-NAMPT crosstalk plays in metastatic breast cancer could lead to new combined therapies that reduce mortality.
- |||||||||| padnarsertib (KPT-9274) / Karyopharm
Trial completion date, Trial primary completion date, Metastases: PAK4 and NAMPT in Patients With Solid Malignancies or NHL (PANAMA) (clinicaltrials.gov) - Jan 29, 2021
P1, N=130, Recruiting,
Given the need for better strategies for improving therapy response of metastatic ER+ tumors, our findings show uncovering the role XPO1-NAMPT crosstalk plays in metastatic breast cancer could lead to new combined therapies that reduce mortality. Trial completion date: May 2021 --> Aug 2021 | Trial primary completion date: May 2021 --> Aug 2021
- |||||||||| padnarsertib (KPT-9274) / Karyopharm
Trial completion date, Trial primary completion date, Metastases: PAK4 and NAMPT in Patients With Solid Malignancies or NHL (PANAMA) (clinicaltrials.gov) - May 4, 2020
P1, N=175, Recruiting,
Taken together, our drug screening approach utilized in silico data to identify potential inhibitors for the treatment of aggressive meningiomas warranting further preclinical investigation. Trial completion date: Nov 2020 --> May 2021 | Trial primary completion date: May 2020 --> May 2021
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