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Neuro-oncology Advances 2024Patients with relapsed or progressive glioblastoma only rarely respond to salvage therapies. Nevertheless, comprehensive genomic profiling can provide insight that can...
BACKGROUND
Patients with relapsed or progressive glioblastoma only rarely respond to salvage therapies. Nevertheless, comprehensive genomic profiling can provide insight that can identify promising approaches. Signaling pathway analyses have revealed synthetic lethal partnerships, which create the possibility of targeting vulnerabilities arising from the loss of tumor suppressor genes. For synthetic lethal vulnerabilities that are not present in normal tissues, lethal cytotoxicity against cancer cells can be achieved without the necessity of causing normal tissue toxicity. This case report describes a patient with progressive glioblastoma with homozygous deletion of chromosome .
METHODS AND RESULTS
Vulnerabilities created by and loss were exploited with pemetrexed, bevacizumab, and candesartan to achieve a clinically meaningful remission by targeting multiple synthetic lethal nodes.
CONCLUSION
Synthetic lethality can reveal the basis for exceptional responsiveness, thus extending the utility of molecular profiling and fulfilling the promise of precision medicine.
PubMed: 38187871
DOI: 10.1093/noajnl/vdad162 -
European Journal of Pharmaceutical... Feb 2024As part of our efforts geared towards developing mechanism-based cancer sensitizing agents, we have previously synthesized and characterized novel deazaflavin analogs as...
As part of our efforts geared towards developing mechanism-based cancer sensitizing agents, we have previously synthesized and characterized novel deazaflavin analogs as potent tyrosyl DNA phosphodiesterase 2 (TDP2) inhibitors for combination treatments with topoisomerase II (TOP2) poisons. Interestingly, the sensitizing effect of a few analogs toward TOP2 poison etoposide (ETP) was associated with a significant increase in intracellular drug accumulation, which could be an alternative mechanism to boost the clinical efficacy of ETP in cancer chemotherapies. Hence, we evaluated more deazaflavin TDP2 inhibitors for their impact on drug retention in cancer cells. We found that all but one tested TDP2 inhibitors substantially increased the ETP retention in DT40 cells. Particularly, we identified an exceptionally potent analog, ZW-1226, which at 3 nM increased the intracellular ETP by 13-fold. Significantly, ZW-1226 also stimulated cellular accumulation of two other anticancer drugs, TOP2 poison teniposide and antifolate pemetrexed, and produced an effect more pronounced than those of ABC transporter inhibitors verapamil and elacridar in human leukemic CCRF-CEM cells toward ETP. Lastly, ZW-1226 potentiated the action of ETP in the sensitive human CCRF-CEM cells and a few resistant non-small-cell lung cancer (NSCLC) cells, including H460 and H838 cells. Collectively, the results of this study strongly suggest that deazaflavin analog ZW-1226 could be an effective cancer sensitizing agent which warrants further investigation.
Topics: Humans; DNA-Binding Proteins; Phosphoric Diester Hydrolases; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Etoposide; DNA Topoisomerases, Type II; Poisons
PubMed: 38159687
DOI: 10.1016/j.ejps.2023.106686 -
Frontiers in Pharmacology 2023Acquired anaplastic lymphoma kinase (ALK) mutation is the major resistant mechanism to ALK tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC)...
Acquired anaplastic lymphoma kinase (ALK) mutation is the major resistant mechanism to ALK tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) patients. At present, treatment options after acquiring secondary ALK mutations are still limited. Here, we report on a patient with metastatic ALK-rearranged NSCLC who was sequentially treated with ALK TKIs, from crizotinib to lorlatinib, and developed rare acquired compound ALK mutations (L1196M and D1203N) that confer resistance to lorlatinib. Moreover, our report describes the clinical response of an NSCLC patient with these compound mutations to multiple anti-tumor therapies. Among them, the patient was treated with SAF-189s 120 mg daily and had a stable disease lasting 3 months. Chemotherapy (pemetrexed-carboplatin) combined with bevacizumab was then administered. She achieved a partial response, which was maintained for 7 months as the best response. Since both SAF-189s and chemotherapy have shown a clear antitumor effect, they may be viable therapeutic options for these patients. Thus, our study can provide some reference in the treatment of NSCLC patients with ALK L1196M/D1203N compound mutations.
PubMed: 38149055
DOI: 10.3389/fphar.2023.1197163 -
Thoracic Cancer Feb 2024Immune checkpoint inhibitors (ICIs) are a revolutionary paradigm in the treatment of thoracic malignancies and chemoimmunotherapy is a current standard care in this...
BACKGROUND
Immune checkpoint inhibitors (ICIs) are a revolutionary paradigm in the treatment of thoracic malignancies and chemoimmunotherapy is a current standard care in this field. Chemotherapeutic agents are known to induce not only direct cytotoxic effects on tumor cells but also immune modulating effects, such as stimulating immunogenic cell death (ICD). Currently, either pemetrexed (PEM) or taxane plus platinum are combined with ICIs for patients with non-small cell lung cancer (NSCLC); however, it is still unknown whether these agents are immunologically optimal partners for ICIs.
METHODS
To determine the immunologically optimal chemotherapeutic agent, we first evaluated the ability of several chemotherapeutic agents, including platinum, PEM, taxane, and 5-fluorouracil (5-FU) to induce ICD using several thoracic tumor cell lines in vitro. ICD was evaluated by the cell surface expression of calreticulin (CRT) and adenosine-triphosphate (ATP) secretion. We further performed an antitumor vaccination assay in vivo.
RESULTS
5-FU induced cell surface expression of CRT and ATP secretion most efficiently among the several chemotherapeutic agents. This effect was enhanced when it was combined with platinum. In the antitumor vaccination assay in vivo, we found that vaccination with dying-AB1-HA (a murine malignant mesothelioma cell line) cells treated with 5-FU, but neither PEM nor PTX, reduced the tumor growth of living-AB1-HA cells inoculated 1 week after vaccination by recruiting CD3 CD8 T cells into the tumor microenvironment.
CONCLUSION
Our findings indicate that fluoropyrimidine can be an immunologically optimal partner of ICIs through the induction of ICD for thoracic malignancies.
Topics: Humans; Animals; Mice; Carcinoma, Non-Small-Cell Lung; Immune Checkpoint Inhibitors; CD8-Positive T-Lymphocytes; Platinum; Immunogenic Cell Death; Lung Neoplasms; Pemetrexed; Antimetabolites; Cell Line, Tumor; Taxoids; Fluorouracil; Adenosine Triphosphate; Tumor Microenvironment
PubMed: 38146645
DOI: 10.1111/1759-7714.15200 -
BMJ Case Reports Dec 2023Malignant peritoneal mesothelioma (MPeM) is a rare malignancy with historically poor prognosis. Recent research has started to reveal increasingly prevalent genetic...
Malignant peritoneal mesothelioma (MPeM) is a rare malignancy with historically poor prognosis. Recent research has started to reveal increasingly prevalent genetic mutations seen in this malignancy. Here, we report a case of complete clinical remission of unresectable, metastatic MPeM with systemic chemotherapy. Immunohistochemistry of our patient's malignant cytology sample showed loss of Breast Cancer Gene 1-associated protein-1 expression (BAP1). The patient had synchronous diagnoses of primary squamous cell carcinoma of the anus, benign schwannoma and meningioma. Following the completion of 18 cycles of pemetrexed and bevacizumab, the patient has remained in clinical remission for 8 months. We examine the unusual susceptibility of unresectable MPeM to systemic chemotherapy and attribute susceptibility to the molecular milieu created by mutations in multiple DNA repair pathways. We encourage increased testing for and analysis of mutations in DNA repair pathways to improve future treatment outcomes in this rare malignancy.
Topics: Humans; Bevacizumab; Pemetrexed; Lung Neoplasms; Mesothelioma, Malignant; Mesothelioma; Peritoneal Neoplasms; Mutation; Ubiquitin Thiolesterase; Tumor Suppressor Proteins
PubMed: 38142057
DOI: 10.1136/bcr-2023-255916 -
Non-coding RNA Research Mar 2024Patients with non-small cell lung cancer (NSCLC) are often treated with chemotherapy. Poor clinical response and the onset of chemoresistance limit the anti-tumor...
Patients with non-small cell lung cancer (NSCLC) are often treated with chemotherapy. Poor clinical response and the onset of chemoresistance limit the anti-tumor benefits of drugs such as cisplatin. According to recent research, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a long non-coding RNA related to cisplatin resistance in NSCLC. Furthermore, MALAT1 targets microRNA-145-5p (miR-145), which activates Krüppel-like factor 4 (KLF4) in associated cell lines. B lymphoma Mo-MLV insertion region 1 homolog (BMI1), on the other hand, inhibits miR-145 expression, which stimulates Specificity protein 1 (Sp1) to trigger the epithelial-mesenchymal transition (EMT) process in pemetrexed-resistant NSCLC cells. The interplay between these molecules in drug resistance is still unclear. Therefore, we propose a dynamic Boolean network that can encapsulate the complexity of these drug-resistant molecules. Using published clinical data for gain or loss-of-function perturbations, our network demonstrates reasonable agreement with experimental observations. We identify four new positive circuits: miR-145/Sp1/MALAT1, BMI1/miR-145/Myc, KLF4/p53/miR-145, and miR-145/Wip1/p38MAPK/p53. Notably, miR-145 emerges as a central player in these regulatory circuits, underscoring its pivotal role in NSCLC drug resistance. Our circuit perturbation analysis further emphasizes the critical involvement of these new circuits in drug resistance for NSCLC. In conclusion, targeting MALAT1 and BMI1 holds promise for overcoming drug resistance, while activating miR-145 represents a potential strategy to significantly reduce drug resistance in NSCLC.
PubMed: 38125755
DOI: 10.1016/j.ncrna.2023.10.008 -
ACS Medicinal Chemistry Letters Dec 2023Pemetrexed and related 5-substituted pyrrolo[2,3-]pyrimidine antifolates are substrates for the ubiquitously expressed reduced folate carrier (RFC), and the...
Pemetrexed and related 5-substituted pyrrolo[2,3-]pyrimidine antifolates are substrates for the ubiquitously expressed reduced folate carrier (RFC), and the proton-coupled folate transporter (PCFT) and folate receptors (FRs) which are more tumor-selective. A long-standing goal has been to discover tumor-targeted therapeutics that draw from one-carbon metabolic vulnerabilities of cancer cells and are selective for transport by FRs and PCFT over RFC. We discovered that a methyl group at the 6-position of the pyrrole ring in the bicyclic scaffold of 5-substituted 2-amino-4-oxo-pyrrolo[2,3-]pyrimidine antifolates - (including pemetrexed) abolished transport by RFC with modest impacts on FRs or PCFT. From molecular modeling, loss of RFC transport involves steric repulsion in the scaffold binding site due to the 6-methyl moiety. 6-Methyl substitution preserved antiproliferative activities toward human tumor cells (KB, IGROV3) with selectivity over IOSE 7576 normal ovary cells and inhibition of purine biosynthesis. Thus, adding a 6-methyl moiety to 5-substituted pyrrolo[2,3-]pyrimidine antifolates affords tumor transport selectivity while preserving antitumor efficacy.
PubMed: 38116433
DOI: 10.1021/acsmedchemlett.3c00326 -
Oncology Letters Jan 2024Lung cancer is the most common type of cancer worldwide. Lung adenocarcinoma, a type of non-small cell lung cancer (NSCLC), is a common type of lung cancer. In recent...
Lung cancer is the most common type of cancer worldwide. Lung adenocarcinoma, a type of non-small cell lung cancer (NSCLC), is a common type of lung cancer. In recent years, immunotherapy has become the primary method of treatment for several solid cancers, including NSCLC. In the present study, the case of a patient with NSCLC following left superior lobectomy is reported. Different systemic therapies failed, such as a pemetrexed + carboplatin regimen, paclitaxel liposome + cisplatin and pembrolizumab, and albumin-bound paclitaxel + toripalimab, but long-term survival was achieved following targeted therapy and anti-programmed cell death protein-1 (PD-1) immunotherapy. The patient survived for >4 years following lung cancer progression, which is notably longer than expected for patients with advanced lung cancer. In conclusion, the present case demonstrated the efficacy of targeted therapy and anti-PD-1 immunotherapy for the treatment of advanced lung cancer following the occurrence of drug resistance and progressive disease.
PubMed: 38108071
DOI: 10.3892/ol.2023.14166 -
Internal Medicine (Tokyo, Japan) Dec 2023A 71-year-old man with advanced lung adenocarcinoma was treated with carboplatin, pemetrexed, and pembrolizumab in June 2020. Pemetrexed and pembrolizumab maintenance...
A 71-year-old man with advanced lung adenocarcinoma was treated with carboplatin, pemetrexed, and pembrolizumab in June 2020. Pemetrexed and pembrolizumab maintenance therapy were continued until November 2022. A fever and severe fatigue occurred in December 2022; however, the cause of the infection was inconclusive based on the patient's symptoms, imaging findings, and culture tests. Although the patient was administered antibiotics, his general condition worsened. Considering the possible diagnosis of immune-related cytokine release syndrome (CRS), the patient was administered prednisolone (1 mg/kg/day) and showed improvement. In conclusion, CRS can occur even long after the initial administration of immune checkpoint inhibitor therapy.
PubMed: 38104995
DOI: 10.2169/internalmedicine.2347-23 -
Case Reports in Oncology 2023C-ros oncogene 1 (ROS1) translocation is an oncogenic driver-mutation identified in 1-2% of non-small-cell lung cancer (NSCLC) cases. Although crizotinib, a tyrosine...
INTRODUCTION
C-ros oncogene 1 (ROS1) translocation is an oncogenic driver-mutation identified in 1-2% of non-small-cell lung cancer (NSCLC) cases. Although crizotinib, a tyrosine kinase inhibitor (TKI) against ALK/ROS1, is known to be effective against ROS1-fusion-positive NSCLC, such cases sometimes progress with brain metastases. The most frequently reported crizotinib-resistance mutation is ROS1 G2032R, and some studies have found that even newly developed ROS1 TKIs, such as entrectinib and lorlatinib, show a decreased efficacy against it. The optimal therapies for ROS1-fusion-positive NSCLC and how such cases can be sequenced have not yet been established.
CASE PRESENTATION
We herein report a patient with ROS1-fusion-positive NSCLC diagnosed at 34 years old. Crizotinib was started at the diagnosis and switched after 25 months to cisplatin/pemetrexed/bevacizumab once the disease progressed with multiple brain metastases that were resistant to stereotactic radiation therapy. The cytotoxic chemotherapy stabilized the patient's condition for 17 months until he developed leptomeningeal metastasis (LM). He underwent lumboperitoneal shunting and whole-brain radiotherapy, followed by crizotinib re-administration. Despite crizotinib treatment, his neurological symptoms, such as double vision, headache, weakness in the legs, and walking difficulties, progressed. Eventually, subsequent entrectinib treatment was initiated, which resolved all of the symptoms mentioned above. Regrettably, liquid next-generation sequencing had failed to detect the resistance mechanism due to minimal ctDNA in this case.
CONCLUSION
These findings imply that sequential entrectinib administration may be effective in patients with disease progression limited to central nervous system metastases during crizotinib administration.
PubMed: 38089732
DOI: 10.1159/000534549