P1, N=110, Recruiting, Lantern Pharma Inc. | Not yet recruiting --> Recruiting | Initiation date: Nov 2023 --> Jan 2023

In preclinical pharmacology studies, the mantle cell lymphoma (MCL) xenograft tumor mouse model derived from JeKo-1, which has mutated TP53 and checkpoint kinase 2 (CHEK2), an HRD score of 46, and was refractory to ibrutinib and bortezomib, showed near complete response after LP-284 treatment. Overall, based on its impressive preclinical anti-tumor efficacy profile, low drug-drug interaction liability, and findings from toxicological studies, a Phase 1 study is currently planned with LP-284 to assess its safety, tolerability, pharmacokinetics, and clinical activity in patients with relapsed or refractory B-cell lymphoma. Clinical development will be informed by an emphasis on patient selection strategy based on DDR/HR biomarkers.

P1, N=110, Not yet recruiting, Lantern Pharma Inc.

As a monotherapy, LP-284 (2 mg/ kg) treatment resulted in 57% TGI, whereas combination treatment with LP-284 (2 mg/kg) and rituximab (10 mg/kg) resulted in 93% TGI. Taken together, our data support further characterization of HRDs in B-NHLs and the development of LP-284 as a targeted B-NHL therapy.

In addition, LP-284 is capable of inhibiting tumor growth of JeKo-1 xenografts that are refractory to bortezomib or ibrutinib. We further showed that LP-284 is particularly lethal in cells with deficient DNA damage response and repair, a targetable vulnerability in NHL.

LP-184, a small-molecule DNA-damaging agent, is known to be synthetically lethal in tumors with DNA-repair deficiencies, including tumors with ATM mutations...These MCL cell lines included cell lines resistant to ibrutinib, zanubrutinib, venetoclax, and bortezomib...Because ATM orchestrates the activities of the NER and HR pathways, MCL patients with ATM deficiencies are likely to have better responses to LP-284 treatment. Collectively, these data indicate that LP-284 is a promising preclinical DNA-damaging agent that possesses nanomolar-range anti-tumor activities in multiple and diverse MCL cell lines, with the potential to treat MCL patients who are resistant to other therapies.

By using an inhibitor of NAD+ recycling, FK866, we show that T cells have reduced NAD+ levels, reduced granzyme B and perforin expression, and even fail to activate in the presence of CD3 and CD28 when NAD+ is limited; however, adding olaparib to these cells rescues the effects of FK866 and allows proliferation and granzyme B production. In vivo we can see that even at olaparib doses that are significantly below those which induce synthetic lethality of tumor cells, olaparib is able to inhibit tumor growth in models of both colorectal and breast cancer. This suggests that olaparib can modulate the activity of T cells directly and has implications for enhancing the anti-tumor activity of these cells both alone and in combination with other forms of immunotherapy.

Comprehensive assessment of HRD status is carried out by combining detection of genetic alterations in HRR genes, genomic instability, mutational signatures, as well as utilisation of genome-wide mutational scar-based HRD classifiers. This in-depth approach has allowed 1) expanded therapeutic options for eligible patients, especially for HRD tumours that carry mutations in noncanonical HRR genes or lack genomic alterations in DDR pathways; 2) better prediction of HRD status and therapy response, especially in tumours carrying HRD gene mutations of unknown significance, or mutations that predict therapy resistance; and 3) identification of resistance mechanisms in non-responder patients.

Overexpression of PKM2 attenuates the CYN-induced DNA damage, mitochondrial fission, and cell viability. Thus, targeting PKM2 provides an original mechanism for understanding the pharmacological impact of CYN and assists in the further development of CYN as an anticancer agent.

We demonstrated the radiosensitizing effects of ENZ on GBM both in vitro and in vivo indicating the potential clinical efficacy treating GBM patients with AR antagonist(s).

These data provide mechanistic evidence for the link between obesity and breast cancer in BRCA1 and BRCA2 mutation carriers through identification of a positive association between BMI and breast epithelial cell DNA damage. Importantly, these studies demonstrate that fulvestrant and metformin, drugs already approved for clinical use, decrease breast epithelial cell DNA damage. Further studies are warranted to determine whether targeting estrogens or use of metformin may be effective risk reduction strategies in BRCA1/2 mutation carriers with excess bodyweight who are at high risk for breast cancer development and currently have limited options for prevention beyond surgical intervention.

Introduction The standard treatment for glioblastoma (GBM) patients is surgical tumor resection, followed by radiation and chemotherapy with temozolomide (TMZ). In orthotopic GBM xenografts, QBS10072S treatment significantly delayed tumorigenesis and prolonged animal survival compared to the vehicle without adverse effects. Conclusion QBS10072S is a novel BBB-permeable chemotherapeutic agent with the potential to treat TMZ-resistant and recurrent GBM as monotherapy or in combination with radiation treatment.

In addition, MGMT has significant implications on chemoresistance and patient survival. Hence, MGMT expression should be mandatorily checked before starting the chemotherapy.

0352-2019-0011 and with the financial support grant of the RFBR and the Kemerovo region in the framework of the scientific project no. 20-44-420012 r_a.

Here, we show that autophagy-deficient liver cancer cells exhibit increased DNA damage caused by the chemotherapeutic agent epirubicin...In the absence of autophagy, the chemosensitivity of liver cancer cells was increased, but this was reversed by MGMT overexpression, indicating that autophagy mediates resistance to chemotherapy in liver cancer cells via MGMT. These findings demonstrate a direct link between autophagy, MGMT, and DNA damage repair in liver cancer cells, and show that MGMT not only regulates chemosensitivity to alkylating agents, but may also be involved in other DNA damage repair processes in autophagy-deficient cells.

Levels of 8OXOG adducts were measured, and significantly increased 8OXOG adduct levels were observed in patients versus controls. These data suggest that deregulation of SIRT3, SIRT4, SIRT5 and OGG1-2a acts as a diagnostic and prognostic marker in leukemia.

Treatment for the lethal primary adult brain tumor glioblastoma (GBM) includes the chemotherapy temozolomide (TMZ), but TMZ resistance is common and correlates with promoter methylation of the DNA repair enzyme O-6-methylguanine-DNA methyltransferase (MGMT). Indeed, SRI-21979, but not haloperidol, significantly reduced the growth of TMZ-resistant GBM cells. Together our data suggest that DRD3 antagonist-based therapies may provide a novel therapeutic option for the treatment of GBM.

In addition, we showed that pentamidine treatment of ZR-75-1 breast cancer cells resulted in reduced proliferation and increased p53 and p21 protein levels, indicating that pentamidine is an effective antagonist that interferes with the S100P-p53 interaction, leading to re-activation of the p53-21 pathway and inhibition of cancer cell proliferation. Collectively, our findings suggest that blocking the association between S100P and p53 by pentamidine will prevent cancer progression and, therefore, provide a new avenue for cancer therapy by targeting the S100P-p53 interaction.

In a set of alleles of known pathogenicity, our assay recapitulated ClinVar's classification; we then estimated pathogenicity for 157 variants classified as uncertain or conflicting reports of significance. This method is capable of studying the mutation rate of many microbial species and can be applied to problems ranging from the generation of high-fidelity polymerases to measuring the frequency of antibiotic resistance emergence.

Moreover, 4AALT3 decreased the level of DNA repair enzyme O-methylguanine-DNA methyltransferase and showed a synergistic effect with temozolomide. Our findings provide the basis for exploring the beneficial effect of 4AALT3 on GBM in vivo.

CF10 is a 2nd generation polymeric fluoropyrimidine (FP) that targets both thymidylate synthase (TS), the target of 5-fluorouracil (5-FU), and DNA topoisomerase 1 (Top1), the target of irinotecan, two drugs that are key components of FOLFIRNOX, a standard of care regimen for pancreatic ductal adenocarcinoma (PDAC). This work moves CF10 closer to a clinical trial for the treatment of PDAC. Implications: CF10 is a promising polymeric fluoropyrimidine with dual mechanisms of action (i.e., TS and Top1 inhibition) for the treatment of PDAC and synergizes with targeting of DNA repair.

A robust understanding of the mechanisms of DDR in SCLC, which exhibits intrinsic replication stress, will improve selection of agents and predictive biomarkers. The most effective combinations will target multiple nodes in the DNA damage/DDR/immune activation cascade to minimize toxicity from synthetic lethality.

These data identify leptin, an adipose-derived hormone, as a novel driver of DNA damage in breast epithelial cells. To date, no studies have elucidated the molecular mechanisms that explain the increased penetrance of breast cancer in obese BRCA mutation carriers compared to lean BRCA mutation carriers. This work suggests that leptin may be a mediator of the link between obesity and breast cancer development in this population.

In the cases of the subgroup carrying the BRCA mutation, the presence of PARP expression was not associated with less favorable relapse rates, but with marginal significance for overall survival predicted a lower chance of survival (OS more than 32 months 72.73% vs. 35%; OR: 0.2; p = 0.05). (4) The BRCA wild type patients with strong expression of PARP enzymes before the first set of chemotherapy have a poor prognosis.

The FOLFOX scheme, based on the association of 5-fluorouracil and oxaliplatin, is the most frequently indicated chemotherapy scheme for patients diagnosed with metastatic colorectal cancer...This constitutes a potential mechanism of epigenetic regulation involved in late-onset of acquired resistance in mCRC patients under FOLFOX chemotherapy. Expression of these biomarker microRNAs could serve as tools for personalized medicine, and as potential therapeutic targets in the future.

Glioblastoma is the most common and aggressive type of cancer in the brain; its poor prognosis is often marked by reoccurrence due to resistance to the chemotherapeutic agent temozolomide, which is triggered by an increase in the expression of DNA repair enzymes such as MGMT...Pharmacological inhibition of DHODH with the specific inhibitors brequinar or ML390 effectively depleted the pool of pyrimidines in glioblastoma cells grown in vitro and in vivo and impaired rDNA transcription, leading to nucleolar stress...Our in vivo data indicate that while inhibition of DHODH caused a dramatic reduction in pyrimidines in tumor cells, it did not affect the overall pyrimidine levels in normal brain and liver tissues, suggesting that pyrimidine production by the salvage pathway may play an important role in maintaining these nucleotides in normal cells. Our study demonstrates that glioblastoma cells heavily rely on the de novo pyrimidine biosynthesis pathway to generate ribosomal RNA (rRNA) and thus, we identified an approach to inhibit ribosome production and consequently the proliferation of glioblastoma cells through the specific inhibition of the de novo pyrimidine biosynthesis pathway.

In detail, we defined EP300 as a panCancer inhibitor of the TIME most likely via metabolic modulation. In this context EP300 represents a promising predictive biomarker and an immuno-therapeutic target.

In contrast, luminal breast cancer and non-transformed mammary cells maintain viability upon POLE suppression but become dependent upon an ATR/CHK1/CDC25A/CDK2 DNA damage response axis. We find that CDK1/2 targets exhibit hyperphosphorylation selectively in BLBC tumors, indicating that CDK2 hyperactivity is a genome integrity vulnerability exploitable by targeting POLE.

Dasatinib DCs with dabrafenib, vemurafenib, or trametinib activated apoptosis and increased cell death in melanoma cells independently of their BRAF status or their drug resistance phenotypes. These preclinical in vitro studies provide a data-driven rationale for the further investigation of DCs between dasatinib and BRAFis or MEKis as candidates for melanoma combination therapies with the potential to improve outcomes and/or prevent or delay the emergence of disease resistance.

Here, we demonstrated that in resistant prostate cancer cells overexpressing EGFR, it was capable of (a) inhibiting EGFR in a dose-dependent manner, (b) damaging DNA, and (c) sustaining the damage by inhibiting the DNA repair protein poly(ADP-ribose) polymerase (PARP). The triple mechanism of action of JS230 cumulated into growth inhibitory potency superior to that of classical two- or three-drug combinations.

High dose melphalan and autologous stem cell transplantation is standard of care for the upfront treatment of multiple myeloma (MM)...We hypothesize that this could be attributed to MYC-related increased gene transcription resulting in DNA damage and RS which in turn recruits several DNA repair pathways. These specific DNA repair pathways and signal activation pathways involved with replication stress represent novel therapeutic targets in myeloma.

KIT/PDGFRA wild-type (WT) gastrointestinal stromal tumors (GISTs) represent a heterogeneous subgroup of GISTs that lack KIT or PDGFRA mutations and possess distinct genetic alterations and primary resistance to imatinib...Moreover, MGMT promoter methylation was identified as a potential independent prognostic factor for OS and DFS in patients with GIST. MGMT promoter methylation is particularly frequent in SDH-deficient GISTs and in WT GISTs possessing an epithelioid/mixed phenotype, and knowledge of this methylation status may offer a novel potential therapeutic option for WT GISTs.

Here we report the design, synthesis, and evaluation of a proteolysis targeting chimaera (PROTAC) based on the combination of PARP-1 inhibitor olaparib and the CRBN (cereblon) ligand lenalidomide. In SW620 cells, our probe-quality degrader compound 2 effectively induced PARP-1 degradation which results in anti-proliferation, cells apoptosis, cell cycle arresting, and cancer cells migratory inhibition. Thus, our findings qualify a new chemical probe for PARP-1 knockdown.

Low mitochondrial OGG1 expression might aggravate the PDAC prognosis.

Legal entity responsible for the study: Laboratory of Pathology "CSD Health Care". Funding: Has not received any funding.

It was found that hmMGMT was suppressed by heavy smoking, and hmMGMT combined with disruptive TP53-mutations may indicate a poor prognosis in patients with HNSCC.

Henceforth nuclear medicine has now advanced towards conjugating theranostic radionuclides to PARP1 inhibitors. This paves the way for a future of PARP1-targeted theranostics and personalized therapy.