indotecan (LMP400) / Gibson Oncology - LARVOL DELTA

Clinical indenoisoquinolines strongly inhibit the global MYC transcriptional pathway (AACR 2025) - "Notably, we found that the clinical LMPs, especially LMP400, exhibited significantly stronger MYC suppression compared to other G4-ligands...In conclusion, we demonstrate that the clinical indenoisoquinolines effectively and persistently inhibit the global MYC transcriptional pathway, serving as a major mechanism of action. Because MYC is a common and essential oncogene, our study provides critical mechanistic understanding and a molecular basis for the future clinical developments and therapeutic applications of indenoisoquinolines in MYC-dependent cancers."

Clinical • Hematological Malignancies • Lymphoma • Oncology • MYC

Treatment with novel topoisomerase inhibitors in Ewing sarcoma models reveals heterogeneity of tumor response. (PubMed, Front Cell Dev Biol) - "In this study, we evaluated the preclinical efficacy of three IIQs (LMP400, LMP744, and LMP776) in relevant models of EWS...LMP400 treatment induced ≥30% tumor regression in two of six PDX models, with more durable regression compared to irinotecan treatment in one of these models...These data, along with pharmacogenomic data on IIQs in sarcoma cell lines, are available at a new interactive public website: https://discover.nci.nih.gov/rsconnect/EwingSarcomaMinerCDB/. Our findings suggest that IIQs may be promising new agents for a subset of EWS patients."

Heterogeneity • Journal • Ewing Sarcoma • Oncology • Sarcoma • Solid Tumor • TOP1

Orphan Designation: Treatment of malignant glioma (FDA) - Date Designated: 10/31/2023

Orphan drug • Brain Cancer • CNS Tumor • Glioma • Oncology • Solid Tumor

Combined inhibition of topoisomerase I and poly(ADP-ribose) polymerase: A synergistic therapeutic strategy for glioblastoma with phosphatase and tensin homolog deficiency. (PubMed, Neurooncol Adv) - "Patient-derived GBM cells and isogenic PTEN-null and PTEN-WT glioma cells were treated with LMP400 (Indotecan), a novel non-camptothecin TOP1 inhibitor alone and in combination with a PARP inhibitor, Olaparib or Niraparib. Animal studies confirmed both an anti-glioma effect and sufficient BBB penetration to prolong survival of mice treated with the drug combination. Our findings provide a proof of concept for the combined treatment with LMP400 and Niraparib in a subset of GBM patients with PTEN deficiency."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor • ABCB1 • ABCG2 • CASP3 • CASP7 • PTEN • TOP1

Dual targeting MYC G-quadruplex and topoisomerase I by indenoisoquinolines for cancer therapy (AACR 2023) - "Three indenoisoquinolines, indotecan (LMP400), indimitecan (LMP776), and LMP744, have entered phase I clinical trials in adults with relapsed solid tumors and lymphomas. Therefore, these results indicate that targeting the MYC promoter G-quadruplex to downregulate MYC is a new mechanism of action for anticancer indenoisoquinolines. Moreover, our data reveals dual targeting of MycG4 and topoisomerase I as a novel strategy for cancer therapy."

Hematological Malignancies • Lymphoma • Oncology • Solid Tumor • TOP1

Evaluating the indotecan-neutropenia relationship in patients with solid tumors by population pharmacokinetic modeling and sigmoidal E regressions. (PubMed, Cancer Chemother Pharmacol) - "The final PK model adequately describes indotecan population pharmacokinetics. Fixed dosing may be justified based on covariate analysis and the weekly dosing regimen may have a reduced neutropenic effect."

Journal • PK/PD data • Hematological Disorders • Neutropenia • Oncology • Solid Tumor

Combined inhibition of TOP1 and PARP: a novel therapeutic strategy for GBM with PTEN deficiency (SNO 2022) - " We used patient-derived GBM cells and stem-like cells to determine response to LMP400 (Indotecan), a novel non-camptothecin TOP1 inhibitor, and the PARP inhibitors Olaparib or Niraparib. Combined inhibition of TOP1 and PARP induces synergistic antiglioma effects selectively in PTEN-null glioblastoma cells, providing a strong scientific premise for a clinical trial of combined treatment with LMP400 and Niraparib in a subset of GBM with PTEN deficiency."

Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor • CASP3 • CASP7 • PTEN • TOP1

Targeting radioresistance and replication fork stability in prostate cancer. (PubMed, JCI Insight) - "We show that the BETi, OTX015, synergizes with the new class of synthetic non-camptothecin TOP1i, LMP400 (indotecan), to block tumor growth in aggressive CRPC xenograft models. Consistent with this observation, TOP1 was highly expressed in metastatic CRPC (mCRPC) and its expression correlated with the expression of BET family genes-BRD4, BRD3 and BRD2. These studies open new avenues for the rational combinatorial treatment of aggressive PCa-particularly, cancers refractory to androgen signaling inhibitors."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • Urology • BRD2 • BRD3 • BRD4 • TOP1

Combined TOP1 and PARP inhibition enforces genomic instability and cell death in PTEN-deficient glioblastoma (SNO 2021) - "CONCLUSION LMP400 and Niraparib act synergistically to target PTEN-deficient glioblastoma by inducing DNA damage and cell death. These results will be further verified in isogenic cells in vitro as well as in vivo in a mouse model driven by PTEN deletion which would strongly support a novel therapeutic strategy in a subset of glioblastoma with PTEN loss."

Brain Cancer • Glioblastoma • Oncology • Solid Tumor • CASP3 • PTEN • TOP1

SLFN11 promotes CDT1 degradation by CUL4 in response to replicative DNA damage, while its absence leads to synthetic lethality with ATR/CHK1 inhibitors. (PubMed, Proc Natl Acad Sci U S A) - "We found that inactivation of Ataxia Telangiectasia- and Rad3-related (ATR), CHK1, BRCA2, and RPA1 overcome chemoresistance to camptothecin (CPT) in SLFN11-KO cells. Accordingly, we validate that clinical inhibitors of ATR (M4344 and M6620) and CHK1 (SRA737) resensitize SLFN11-KO cells to topotecan, indotecan, etoposide, cisplatin, and talazoparib...Taken together, our study reveals new chemotherapeutic insights on how targeting the ATR pathway overcomes chemoresistance of SLFN11-deficient cancers. It also demonstrates that SLFN11 irreversibly arrests replication by degrading CDT1 through the DDB1-CUL4 ubiquitin ligase."

Journal • Ataxia • Immunology • Movement Disorders • Oncology • Primary Immunodeficiency • Targeted Protein Degradation • BRCA2 • CHEK1 • DDB1 • RPA1 • SLFN11

The indenoisoquinoline TOP1 inhibitors selectively target homologous recombination deficient- and Schlafen 11-positive cancer cells and synergize with olaparib. (PubMed, Clin Cancer Res) - "Our results provide a rationale for molecularly designed clinical trials with the indenoisoquinolines as single agents and in combination with PARP inhibitors in HRD cancers expressing SLFN11."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Targeting Topoisomerase I in the Era of Precision Medicine. (PubMed, Clin Cancer Res) - "Irinotecan and topotecan have been widely used as anticancer drugs for the past 20 years. We introduce new therapeutic strategies based on novel TOP1 inhibitor chemical scaffolds including the indenoisoquinolines LMP400 (indotecan), LMP776 (indimitecan) and LMP744, and on tumor-targeted delivery TOP1 inhibitors (TTTis) using liposome, PEGylation and antibody-drug conjugates. We also address how tumor-specific determinants such as homologous recombination defects (HRD and BRCAness) and Schlafen 11 (SLFN11) expression can be used to guide clinical application of TOP1 inhibitors in combination with DNA damage response inhibitors including PARP, ATR, CHEK1 and ATM inhibitors."

Journal • Oncology

[VIRTUAL] The novel ATR inhibitor M4344 and CHK1 inhibitor SRA737 overcome chemoresistance in SLFN11-negative cells in combination treatment with DNA-damaging agents (AACR-II 2020) - "To identify synthetic lethal therapeutic targets to overcome chemoresistance in SLFN11 deficient cells, we performed a genome-wide RNAi screen with the human druggable genome siRNA library by using camptothecin (CPT), a TOP1 inhibitor, in SLFN11 wild-type (WT) and knock-out (KO) prostate cancer DU145 cells...Treatment with non-toxic-doses of M4344 and SRA737 reversed drug resistance of the SLFN11 KO cells to TOP1 inhibitors [CPT, and clinically used topotecan and LMP400 (indotecan)]...We also confirmed synergy with ATR/CHK1 inhibitors in combination of other clinical DNA-damaging agents (TOP2 inhibitor: etoposide, alkylating agent: cisplatin, and PARP inhibitor: talazoparib)...Co-treatment with ATR inhibitor and CPT resulted in G2/M arrest and apoptotic cell death, and formation of micronuclei and fragmented nuclei in SLFN11 KO cells, compared with SLFN11 WT cells. Collectively, our results provide a new therapeutic rationale for the clinical development of combination..."

Late-breaking abstract • Genito-urinary Cancer • Lung Cancer • Oncology • Prostate Cancer • Small Cell Lung Cancer • Solid Tumor • Thoracic Cancer • ATR • BRCA2 • RPA1 • SLFN11 • TOP1

[VIRTUAL] Dual targeting MYC G-quadruplex and topoisomerase I: Lead discovery indenoisoquinolines for cancer therapy (AACR-II 2020) - "Indenoisoquinolines are human topoisomerase I inhibitors with improved physicochemical and biological properties as compared to the clinically used camptothecin anticancer drugs. Three indenoisoquinolines, indotecan (LMP400), indimitecan (LMP776), and LMP744, have entered phase I clinical trials in adults with relapsed solid tumors and lymphomas...In conclusion, our result reveals MYC downregulation by MycG4 binding as a new mechanism of action for anticancer indenoisoquinolines. Moreover, we suggest dual targeting of MycG4 and topoisomerase I as a novel strategy for cancer therapy."

Hematological Malignancies • Oncology • Solid Tumor • PCR • TOP1

The indenoisoquinoline LMP517: a novel antitumor agent targeting both TOP1 and TOP2. (PubMed, Mol Cancer Ther) - "The camptothecin derivatives topoisomerase I (TOP1) inhibitors, irinotecan and topotecan are US-FDA approved for the treatment of colorectal, ovarian, lung and breast cancers. Because of the chemical instability of camptothecins, short plasma half-life, drug efflux by the multidrug-resistance ABC transporters and the severe diarrhea produced by irinotecan, indenoisoquinoline TOP1 inhibitors (LMP400, LMP776 and LMP744), which overcome these limitations, have been developed and are in clinical development...Histone γH2AX detection showed that, unlike classical TOP1 inhibitors, LMP517 targets cells independently of their position in the cell cycle. Our study establishes LMP517 as a dual TOP1 and TOP2 inhibitor with therapeutic potential."

Journal • Breast Cancer • Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor • Thoracic Cancer • TOP1 • XRCC6

BRCAness, SLFN11, and RB1 loss predict response to topoisomerase I inhibitors in triple-negative breast cancers. (PubMed, Sci Transl Med) - "In addition, the combination of irinotecan and the ataxia telangiectasia and Rad3-related protein (ATR) inhibitor VE-822 was tested in SLFN11-negative PDXs, and two clinical non-camptothecin TOP1 inhibitors (LMP400 and LMP776) were tested. In conclusion, a substantial proportion of TNBC respond to irinotecan. BRCAness, high SLFN11 expression, and RB1 loss are highly predictive of response to irinotecan and the clinical indenoisoquinoline TOP1 inhibitors."

Journal • ATR • BRCA1 • CHEK1 • PCR • RB1 • SLFN • TOP1

NCI Comparative Oncology Program Testing of Non-Camptothecin Indenoisoquinoline Topoisomerase I Inhibitors in Naturally Occurring Canine Lymphoma. (PubMed, Clin Cancer Res) - "These results demonstrate proof-of-mechanism for indenoisoquinoline TOP1 inhibitors supporting their further clinical development. They also highlight the value of the NCI Comparative Oncology Program (https://ccr.cancer.gov/Comparative-Oncology-Program) for evaluating novel therapies in immune-competent pets with cancers."

Journal

Novel fluoroindenoisoquinoline non-camptothecin topoisomerase I inhibitors. (PubMed, Mol Cancer Ther) - "Contrary to other anticancer targets, topoisomerase I (TOP1) is targeted by only one chemical class of FDA-approved drugs: topotecan and irinotecan, the derivatives of the plant alkaloid, camptothecin. The indenoisoquinolines LMP400, LMP744, and LMP776 are novel noncamptothecin TOP1 inhibitors in clinical trial, which overcome the limitations of camptothecins...Genomic analyses and activity assays in CCRF-CEM SLFN11-deleted cells showed that SLFN11 expression is a dominant determinant of response to LMP135. This study shows the potential value of the fluoroindenoisoquinolines for further development as novel anticancer agents targeting TOP1."

Journal

Indotecan (LMP400), indimitecan (LMP776) and LMP744, a new class of non-camptothecin topoisomerase I inhibitors selective for schlafen11-positive and BRCA-deficient cells that synergize with olaparib (AACR 2019) - "To overcome the limitations of topoisomerase inhibitors, irinotecan and topotecan (chemical instability, drug efflux substrates, short half-life, dose-limiting bone marrow and gastrointestinal toxicity), we have developed the indenoisoquinolines (LMP400, LMP776 and LMP744). Better efficacy was observed with the combination over single agent treatments of LMP400 or olaparib. Our results provide a rationale for Phase 2 indenoisoquinoline clinical trials with the indenoisoquinolines in HR-deficient cancers as single agents and in combination with PARP inhibitors, and for measuring Schlafen 11 (SLFN11) as a clinical response determinant."