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Frontiers in Oncology 2023A series of seven clinical trials on relapsed or refractory (r/r) metastatic neoplasias followed the question: Are networks of ligand-receptor cross-talks that support... (Review)
Review
A series of seven clinical trials on relapsed or refractory (r/r) metastatic neoplasias followed the question: Are networks of ligand-receptor cross-talks that support tumor-specific cancer hallmarks, druggable with tumor tissue editing approaches therapeutically exploiting tumor plasticity? Differential recombinations of pioglitazone, a dual peroxisome-proliferator activated receptor (PPARα/γ) agonist, with transcriptional modulators, i.e., all-trans retinoic acid, interferon-α, or dexamethasone plus metronomic low-dose chemotherapy (MCT) or epigenetic modeling with azacitidine plus/minus cyclooxygenase-2 inhibition initiated tumor-specific reprogramming of cancer hallmarks, as exemplified by inflammation control in r/r melanoma, renal clear cell carcinoma (RCCC), Hodgkin's lymphoma (HL) and multisystem Langerhans cell histiocytosis (mLCH) or differentiation induction in non-promyelocytic acute myeloid leukemia (non-PML AML). Pioglitazone, integrated in differentially designed editing schedules, facilitated induction of tumor cell death as indicated by complete remission (CR) in r/r non-PML AML, continuous CR in r/r RCCC, mLCH, and in HL by addition of everolimus, or long-term disease control in melanoma by efficaciously controlling metastasis, post-therapy cancer repopulation and acquired cell-resistance and genetic/molecular-genetic tumor cell heterogeneity (M-CRAC). PPARα/γ agonists provided tumor-type agnostic biomodulatory efficacy across different histologic neoplasias. Tissue editing techniques disclose that wide-ranging functions of PPARα/γ agonists may be on-topic focused for differentially unlocking tumor phenotypes. Low-dose MCT facilitates targeted reprogramming of cancer hallmarks with transcriptional modulators, induction of tumor cell death, M-CRAC control and editing of non-oncogene addiction. Thus, pioglitazone, integrated in tumor tissue editing protocols, is an important biomodulatory drug for addressing urgent therapeutic problems, such as M-CRAC in relapsed or refractory tumor disease.
PubMed: 38273846
DOI: 10.3389/fonc.2023.1289222 -
Cancers Dec 2023The concept of post-therapy metastatic spread, cancer repopulation and acquired tumor cell resistance (M-CRAC) rationalizes tumor progression because of tumor cell... (Review)
Review
The concept of post-therapy metastatic spread, cancer repopulation and acquired tumor cell resistance (M-CRAC) rationalizes tumor progression because of tumor cell heterogeneity arising from post-therapy genetic damage and subsequent tissue repair mechanisms. Therapeutic strategies designed to specifically address M-CRAC involve tissue editing approaches, such as low-dose metronomic chemotherapy and the use of transcriptional modulators with or without targeted therapies. Notably, tumor tissue editing holds the potential to treat patients, who are refractory to or relapsing (r/r) after conventional chemotherapy, which is usually based on administering a maximum tolerable dose of a cytostatic drugs. Clinical trials enrolling patients with r/r malignancies, e.g., non-small cell lung cancer, Hodgkin's lymphoma, Langerhans cell histiocytosis and acute myelocytic leukemia, indicate that tissue editing approaches could yield tangible clinical benefit. In contrast to conventional chemotherapy or state-of-the-art precision medicine, tissue editing employs a multi-pronged approach targeting important drivers of M-CRAC across various tumor entities, thereby, simultaneously engaging tumor cell differentiation, immunomodulation, and inflammation control. In this review, we highlight the M-CRAC concept as a major factor in resistance to conventional cancer therapies and discusses tissue editing as a potential treatment.
PubMed: 38201607
DOI: 10.3390/cancers16010180 -
European Journal of Cancer (Oxford,... Feb 2024This multicenter Phase I study (NCT03585465) evaluated nivolumab in combination with 3 metronomic chemotherapy (MC) regimens in children with refractory/relapsing solid...
BACKGROUND
This multicenter Phase I study (NCT03585465) evaluated nivolumab in combination with 3 metronomic chemotherapy (MC) regimens in children with refractory/relapsing solid tumors.
OBJECTIVES
To evaluate the feasibility and safety of the three regimens METHODS: Patients aged < 18 years were enrolled. Nivolumab was combined with cyclophosphamide and vinblastine (arm A), capecitabine (arm B), or cyclophosphamide, vinblastine and capecitabine (arm C). Arm A and B were allocated sequentially. Arm C opened only if A and B were deemed safe. Dose-limiting toxicities (DLTs) were evaluated over the first two cycles. Patients were evaluable if they received > 2 cycles and > 70% of the planned dose.
POPULATION
Sixteen patients were enrolled, 3 in arm A, 6 in arm B, and 7 in arm C. Median age was 11.5 years (range, 5-19). Patients previously received a median of 3.5 (range, 1-4) lines of systemic treatment, 14 patients had surgery and 11 had radiotherapy.
RESULTS
Median number of cycles was 2 (1-24), median treatment duration was 56 days (18-714). In arm C, median number of cycles was 4 with median treatment duration of 95 days. No DLT was observed. Grade 3 adverse events (AE) and serious AE were observed in 8 patients (50%) and 1 patient (6%), respectively, over the first 2 cycles. No grade 4 AE occurred. The 6-month PFS and OS were 12% and 44%, respectively, in the whole population. Prolonged stable disease was observed in a high-grade glioma and an atypical teratoid rhabdoid tumor.
CONCLUSION
Arm C appears safe. A randomized phase II trial evaluating the addition of nivolumab to the triple MC is ongoing.
Topics: Adolescent; Child; Humans; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Cyclophosphamide; Neoplasm Recurrence, Local; Nivolumab; Vinblastine; Child, Preschool
PubMed: 38199147
DOI: 10.1016/j.ejca.2024.113525 -
Cureus Dec 2023Treatment of locally advanced oral cancer requires multidisciplinary care, including surgery, radiotherapy, and chemotherapy, which varies based on the stage of the... (Review)
Review
Treatment of locally advanced oral cancer requires multidisciplinary care, including surgery, radiotherapy, and chemotherapy, which varies based on the stage of the disease, site of involvement, and surgical access. Oral cancer usually presents with an increased recurrence rate and potential for distant metastatic spread. It confers a poor prognosis with a 50% mortality rate after five years. Oral metronomic chemotherapy aims to achieve higher patient compliance due to its ease of administration, lower dosage, and lesser side effects than conventional IV regimens of platinum-based drugs. In this review, we have summarized the relevant literature to benefit the readers regarding the potential application of metronomic therapy in the management of oral cancer.
PubMed: 38169679
DOI: 10.7759/cureus.49825 -
BMC Research Notes Jan 2024Metformin is a widely used antidiabetic biguanide. Retrospective data demonstrated the association of metformin use with survival benefit in multiple tumor types....
Metformin is a widely used antidiabetic biguanide. Retrospective data demonstrated the association of metformin use with survival benefit in multiple tumor types. Interest in repurposing metformin to treat cancer has not been translated into encouraging clinical benefit. In animal models, metformin activated cytotoxic T cells and exerted an immune-mediated anticancer effect. The current research was conducted to investigate the possible therapeutic benefit of metformin in combination with metronomic cyclophosphamide in an experimental cancer model. Ehrlich ascites carcinoma was injected into the subcutaneous tissue to induce solid tumors in syngeneic mice. Exponential solid tumor growth ensued and was effectively arrested with the administration of a cytotoxic dose of parenteral cyclophosphamide. Alternatively, oral metformin and continuous, low-dose cyclophosphamide significantly inhibited tumor growth relative to untreated mice. The drug combination was well tolerated. Histopathological examination of the tumor showed an increased number of tumor-infiltrating lymphocytes and enhanced expression of granzyme B by this drug combination. The current data suggests a potential role of metformin and metronomic chemotherapy that warrants further investigation.
Topics: Mice; Animals; Lymphocytes, Tumor-Infiltrating; Metformin; Retrospective Studies; Administration, Metronomic; Cyclophosphamide; Carcinoma; Drug Combinations; Cell Line, Tumor
PubMed: 38167322
DOI: 10.1186/s13104-023-06651-1 -
Medical Oncology (Northwood, London,... Dec 2023Pantoprazole decreases the acidity of the tumor microenvironment by inhibiting proton pumps on the cancer cell. This possibly leads to increased sensitivity to... (Randomized Controlled Trial)
Randomized Controlled Trial
Pantoprazole decreases the acidity of the tumor microenvironment by inhibiting proton pumps on the cancer cell. This possibly leads to increased sensitivity to cytotoxic therapy. We conducted a phase I/II randomized controlled trial in adult patients with head and neck squamous cell carcinoma (HNSCC) planned for first-line palliative chemotherapy. Patients were randomized to chemotherapy + / - intravenous (IV) pantoprazole. The primary endpoint in phase I was to determine the maximum safe dose of intravenous pantoprazole, whereas it was progression-free survival (PFS) in phase II. The dose of IV pantoprazole established in phase I was 240 mg. Between Nov'18 and Oct'20, we recruited 120 patients in phase II, 59 on pantoprazole and 61 on the standard arm. Median age was 51 years (IQR 43-60), 80% were men. Systemic therapy was IV cisplatin in 22% and oral-metronomic-chemotherapy (OMC) in 78%. Addition of pantoprazole did not prolong PFS, which was 2.2 months (95% CI 2.07-3.19) in the pantoprazole arm and 2.5 months (95% CI 2.04-3.81, HR, 1.14; 95% CI 0.78-1.66; P = 0.48) in the standard arm. Response rates were similar; pantoprazole arm 8.5%, standard arm 6.6%; P = 0.175. Overall survival was also similar; 5.6 months (95% CI 4.47-8.51) in the pantoprazole arm and 5.4 months (95% CI 3.48-8.54, HR 1.06; 95% CI 0.72-1.57; P = 0.75) in the standard arm. Grade ≥ 3 toxicities were similar. Thus, pantoprazole 240 mg IV added to systemic therapy does not improve outcomes in patients with advanced HNSCC.
Topics: Adult; Male; Humans; Middle Aged; Female; Squamous Cell Carcinoma of Head and Neck; Pantoprazole; Carcinoma, Squamous Cell; Head and Neck Neoplasms; Cisplatin; Antineoplastic Combined Chemotherapy Protocols; Tumor Microenvironment
PubMed: 38129716
DOI: 10.1007/s12032-023-02234-z -
Clinical Genitourinary Cancer Apr 2024Despite the introduction of various novel therapies for management of metastatic castrate resistant prostate cancer (mCRPC) in recent decades, available treatment...
INTRODUCTION
Despite the introduction of various novel therapies for management of metastatic castrate resistant prostate cancer (mCRPC) in recent decades, available treatment options are finite and remain limited. Multiple historical studies have demonstrated activity and a favorable toxicity profile of oral metronomic cyclophosphamide (mCyc) in prostate cancer (PCa). Unlike the cytotoxic immunosuppressive effects of high-dose intravenously-administered cyclophosphamide, continuous low doses of oral mCyc have a unique immune-stimulatory mechanism of action.
MATERIALS AND METHODS
This is a retrospective, multi-institution study of men with 43 patients with mCRPC treated mCyc. Patient demographic information as well as clinical, pathologic, and genomic characteristics of their PCa were extracted. The primary endpoint was the rate of PSA decline by ≥ 50% (ie, PSA50). Additional efficacy and toxicity data as well as cost analysis compared to other commonly used agents in mCRPC was obtained.
RESULTS
PSA50 was noted in 20.9% of patients, while an additional 25.6% patients achieved < PSA50 and 6.9% reported improvement in prostate cancer-related symptoms without any PSA reduction. Meanwhile, 9.3% of patients required mCyc dose reduction, 11.6% needed dose interruption due to toxicity, and no treatment discontinuations due to toxicity were observed. mCyc was also cost effective compared to other agents commonly used in mCRPC.
CONCLUSIONS
Despite the small sample size and retrospective nature of this dataset, mCyc demonstrated promising rapid activity and a tolerable toxicity profile in a heavily pretreated mCRPC population with aggressive clinical, pathologic, and genomic disease features.
Topics: Male; Humans; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Treatment Outcome; Cyclophosphamide
PubMed: 38087703
DOI: 10.1016/j.clgc.2023.11.002 -
International Journal of Oncology Feb 2024Metronomic chemotherapy (MCT) regimens may be associated with risks to the patient due to the ambiguity surrounding low dosages and schedules. In the present study,...
Metronomic chemotherapy (MCT) regimens may be associated with risks to the patient due to the ambiguity surrounding low dosages and schedules. In the present study, metronomic regimens of vinorelbine (NVB) combined with cisplatin (CDDP) or fluorouracil (5‑FU) were chosen to study the dose‑response associations with tumor growth and metastasis, along with the underlying mechanisms in angiogenesis, apoptosis and tumor immunity, using experimental techniques such as immunofluorescence, immunohistochemistry, western blotting and flow cytometry. The results demonstrated a dual‑directional pharmacological action of promoting and suppressing tumor growth or metastasis in BALB/c mice bearing a 4T1 tumor at certain low and high doses of the drugs. Low doses of NVB combined with CDDP or 5‑FU accelerated tumor growth by enhancing angiogenesis, increasing the expression of angiogenic proteins, NF‑κB and osteopontin in tumor tissues, and inducing the accumulation of myeloid‑derived suppressor cells and macrophages. By contrast, higher doses inhibited tumor growth by suppressing these effects. Notably, the upregulation of apoptotic proteins was observed after low‑ and high‑dose treatments. Furthermore, at low concentrations, NVB combined with CDDP or 5‑FU stimulated certain functions of endothelial and tumor cells, including migration and invasion, whereas at higher concentrations they suppressed proliferation and induced apoptosis. Therefore, the results of the present study suggested the potential risks of metronomic combination chemotherapy by demonstrating that, at certain low doses, tumor growth or metastasis was promoted, and emphasized the existence of an effective dose interval that changes with different drug combinations. However, further studies are needed before a specific metronomic combination regimen can be administered clinically for cancer treatment.
Topics: Mice; Animals; Humans; Female; Vinorelbine; Breast Neoplasms; Fluorouracil; Cisplatin; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Administration, Metronomic
PubMed: 38063236
DOI: 10.3892/ijo.2023.5601 -
Scientific Reports Dec 2023Rhabdoid tumors are aggressive tumors that may arise in the kidney, soft tissue, central nervous system, or other organs. They are defined by SMARCB1 (INI1) or SMARCA4...
Rhabdoid tumors are aggressive tumors that may arise in the kidney, soft tissue, central nervous system, or other organs. They are defined by SMARCB1 (INI1) or SMARCA4 alterations. Often, very young children are affected, and the prognosis is dismal. Four patients with primary atypical teratoid rhabdoid tumor (AT/RT, a rhabdoid tumor in the central nervous system) were treated by resection and high dose chemotherapy. Tazemetostat was introduced after completion of chemotherapy. Three patients have achieved an event free survival of 32, 34, and 30 months respectively. One progressed and died. His overall survival was 20 months. One patient was treated for a relapsed atypical teratoid rhabdoid tumor. The treatment combined metronomic therapy, radiotherapy, tazemetostat and immunotherapy. This patient died of disease progression, with an overall survival of 37 months. One patient was treated for a rhabdoid tumor of the ovary. Tazemetostat was given as maintenance after resection, chemotherapy, and radiotherapy, concomitantly with immunotherapy. Her event free survival is 44 months. Only approximately 40% of patients with rhabdoid tumors achieve long-term survival. Nearly all relapses occur within two years from diagnosis. The event free survival of four of the six patients in our cohort has exceeded this timepoint. Tazemetostat has been mostly tested as a single agent in the relapsed setting. We present promising results when applied as maintenance or add on in the first line treatment.
Topics: Humans; Child; Female; Infant; Child, Preschool; Rhabdoid Tumor; Neoplasm Recurrence, Local; SMARCB1 Protein; Teratoma; Central Nervous System Neoplasms; DNA Helicases; Nuclear Proteins; Transcription Factors
PubMed: 38062114
DOI: 10.1038/s41598-023-48774-2 -
The Lancet. Oncology Dec 2023
Topics: Humans; Neoplasms; Precision Medicine; Medical Oncology; Molecular Targeted Therapy
PubMed: 38039994
DOI: 10.1016/S1470-2045(23)00476-X