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RRx-001 is an anticancer agent that subjects cancer cells to reactive oxygen/nitrogen species (ROS/RNS) and acts as an epigenetic modifier. We have used a thiol-bearing MRI contrast agent, Gd-LC7-SH, to investigate the pharmacodynamics of RRx-001 in CHP-100 Ewing's Sarcoma, HT-29 colorectal carcinoma, and PANC-1 pancreatic carcinoma xenografts in SCID mice. Binding of Gd-LC7-SH to the Cys34 residue on plasma albumin prolongs retention in the tumor microenvironment and increases tumor enhancement on MRI. Mice were imaged by MRI and in vivo T1 maps acquired 50 min (T150 min) after injection of 0.05 mmol/kg Gd-LC7-SH (i.v.) at baseline and 1, 24, and 72 h post-treatment with 10 mg/kg RRx-001 (i.v.). Consistent with an indirect thiol-modifying activity of RRx-001, tumor T150 min at 1 h post-drug was significantly longer than pre-drug tumor T150 min in all three tumor models, with the T150 min remaining significantly longer than baseline through 72 h post-drug in the HT-29 and PANC-1 tumors. The T150 min of CHP-100 tumors recovered to baseline by 24 h post-drug, suggesting a robust anti-oxidant response to the RRx-001 challenge that was presaged by a marked increase in perfusion at 1 h post-drug measured by DCE-MRI. MRI enhanced with Gd-LC7-SH provides a mechanistically rational biomarker of RRx-001 pharmacodynamics.
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Checkpoint inhibitors, monoclonal antibodies that inhibit PD-1 or CTLA-4, have revolutionized the treatment of multiple cancers. Despite the enthusiasm for the clinical successes of checkpoint inhibitors, and immunotherapy, in general, only a minority of patients with specific tumor types actually benefit from treatment. Emerging evidence implicates epigenetic alterations as a mechanism of clinical resistance to immunotherapy. This review presents evidence for that association, summarizes the epi-based mechanisms by which tumors evade immunogenic cell death, discusses epigenetic modulation as a component of an integrated strategy to boost anticancer T cell effector function in relation to a tumor immunosuppression cycle and, finally, makes the case that the success of this no-patient-left-behind strategy critically depends on the toxicity profile of the epigenetic agent(s).
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BACKGROUND: RRx-001, a dinitroazetidine derivative, is a novel anticancer agent currently in phase II clinical trials. It mediates immunomodulatory effects either directly through polarization of tumor associated macrophages or indirectly through vascular normalization and increased T-lymphocyte infiltration. With multiple additional mechanisms of action including upregulation of oxidative stress, depletion of GSH and NADPH, anti-angiogenesis and epigenetic modulation, RRx-001 is being studied as a radio- and chemo-sensitizer to resensitize tumors to prior therapy and to prime tumors to respond to radiation, chemotherapy and immunotherapy in combination therapy studies. Here, we identified another mechanism, viral mimicry, which refers to the "unsilencing" of epigenetically repressed viral genes present in the tumor that provokes an immune response and may contribute to the anticancer activity of RRx-001. RESULTS: RRx-001 inhibited the growth of colon cancer cells (HCT 116) and decreased levels of the DNA methyltransferases DNMT1 and DNMT3a in a time and dose-dependent manner. Treatment of HCT 116 cells with 0.5 µM RRx-001 for 24 h significantly increased transcripts of interferon (IFN)-responsive genes and this induction was sustained for up to 4 weeks after transient exposure to RRx-001. ELISA assays showed that RRx-001 increased secretion of type I and III IFNs by HCT 116 cells, and these IFNs were confirmed to be bioactive. Transcription of endogenous retrovirus ERV-Fc2 and LTRs from the ERV-L family (MLT2B4 and MLT1C49) was induced by RRx-001. The induction of ERV-Fc2-env was through demethylation of ERV-Fc2 LTR as determined by methylation-specific polymerase chain reaction and combined bisulfite restriction analysis. Immunofluorescence staining with J2 antibody confirmed induction of double-stranded RNA. CONCLUSIONS: Transient exposure of HCT 116 cells to low-dose RRx-001 induced transcription of silenced retroviral genes present in the cancer cell DNA with subsequent synthesis of IFN in response to this "pseudo-pathogenic" stimulus, mimicking an antiviral defense. RRx-001-mediated IFN induction may have the potential to improve the efficacy of immunotherapies as well as radiotherapy, standard chemotherapies and molecularly targeted agents when used in combination. The striking safety profile of RRx-001 in comparison to other more toxic epigenetic and immunomodulatory agents such as azacitidine makes it a leading candidate for such clinical applications.
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Azetidinas/farmacología , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/inmunología , Interferones/inmunología , Nitrocompuestos/farmacología , Antineoplásicos/farmacología , Azacitidina/farmacología , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Neoplasias del Colon/enzimología , Neoplasias del Colon/genética , ADN (Citosina-5-)-Metiltransferasa 1 , ADN (Citosina-5-)-Metiltransferasas/metabolismo , ADN Metiltransferasa 3A , Relación Dosis-Respuesta a Droga , Regulación hacia Abajo/efectos de los fármacos , Retrovirus Endógenos/genética , Retrovirus Endógenos/inmunología , Epigénesis Genética/efectos de los fármacos , Células HCT116 , Humanos , Factores Inmunológicos/farmacología , Interferones/biosíntesis , Interferones/genética , Imitación Molecular , Transcripción Genética , Proteínas del Envoltorio Viral/genética , Proteínas del Envoltorio Viral/inmunologíaRESUMEN
INTRODUCTION: According to Hanahan and Weinberg, cancer manifests as six essential physiologic hallmarks: (1) self-sufficiency in growth signals, (2) insensitivity to growth-inhibitory signals, (3) evasion of programmed cell death, (4) limitless replicative potential, (5) sustained angiogenesis, and (6) invasion and metastasis. As a facilitator of these traits as well as immunosuppression and chemoresistance, the presence of tumor-associated macrophages (TAMs) may serve as the seventh hallmark of cancer. Anticancer agents that successfully reprogram TAMs to target rather than support tumor cells may hold the key to better therapeutic outcomes. Areas covered: This article summarizes the characteristics of the macrophage-stimulating agent RRx-001, a molecular iconoclast, sourced from the aerospace industry, with a particular emphasis on the cell-to-cell transfer mechanism of action (RBCs to TAMs) underlying its antitumor activity as well as its chemo and radioprotective properties, consolidated from various preclinical and clinical studies. Expert opinion: RRx-001 is macrophage-stimulating agent with the potential to synergize with chemotherapy, radiotherapy and immunotherapy while simultaneously protecting normal tissues from their cytotoxic effects. Given the promising indications of activity in multiple tumor types and these normal tissue protective properties, RRx-001 may be used to treat a broad spectrum of malignancies, if it is approved in the future.
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Azetidinas/uso terapéutico , Macrófagos/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Nitrocompuestos/uso terapéutico , Animales , Antineoplásicos/efectos adversos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Azetidinas/efectos adversos , Azetidinas/farmacología , Muerte Celular/efectos de los fármacos , Resistencia a Antineoplásicos , Humanos , Macrófagos/metabolismo , Neoplasias/patología , Nitrocompuestos/efectos adversos , Nitrocompuestos/farmacologíaRESUMEN
BACKGROUND: The response to first-line platinum doublets (cisplatin/etoposide) in small-cell lung cancer (SCLC) predicts the probability of subsequent response to second-line therapy. In general, the longer-lived the responses in first line, the better the outcome in second line, with the opposite prognosis for shorter-lived responses. Resistant SCLC is defined as relapse within 90 days of platinum-doublet treatment, and predictably correlates with shortened survival compared with sensitive disease, defined as relapse after 90 days. CASE REPORT: We present a patient with platinum-resistant SCLC that was rechallenged with cisplatin/etoposide in the context of the clinical trial TRIPLE THREAT (NCT02489903) after treatment with, and progression on, the resistance-reversing anticancer agent RRx-001. CONCLUSION: The prolonged partial response of this platinum-resistant SCLC to reintroduced carboplatin/etoposide after RRx-001 belies and contradicts the prevailing orthodoxy in oncology that rechallenge with chemotherapy after the emergence of resistance is an exercise in futility and risk, which potentially exposes patients to toxicity without benefit.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Azetidinas/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Cisplatino/administración & dosificación , Etopósido/administración & dosificación , Neoplasias Pulmonares/tratamiento farmacológico , Nitrocompuestos/administración & dosificación , Esquema de Medicación , Resistencia a Antineoplásicos/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
As an exceedingly recalcitrant and highly aggressive tumor type without Food and Drug Administration-approved treatment or a known cure, the prognosis of recurrent extensive stage platinum-resistant/refractory small cell lung cancer (SCLC) is worse than other types of lung cancer, and many other tumor types, given a response rate of less than 10% and an overall survival of less than six months. It was broadly classified into three groups based on the initial response to cisplatin/etoposide therapy, platinum-refractory, platinum-resistant, and platinum-sensitive, extensive stage SCLC inevitably relapses, at which point the only standard options are to rechallenge with the first-line chemotherapeutic regimen in the case of sensitive disease or to start the topoisomerase I inhibitor, topotecan. Sensitive disease is defined by a response to the first-line therapy and a treatment-free interval of at least 90 days, while the definitions of refractory and resistant disease, respectively, are nonresponse to the first-line treatment or relapse within 90 days. As an important predictor of response to the second-line treatment, the clinical cutoff of three months (or two months in some cases) for resistant and sensitive disease, which along with performance status prognostically separates patients into high- and low-risk categories, dictates subsequent management. This case report presents a resistant SCLC patient enrolled on a Phase II clinical trial called QUADRUPLE THREAT (formerly TRIPLE THREAT; NCT02489903) who responded to reintroduced platinum doublets after sequential priming with the resistance-reversing epi-immunotherapeutic agent, RRx-001. In the QUADRUPLE THREAT clinical trial, both during priming with RRx-001 and during sequential treatment with platinum doublets, the patient maintained a good quality of life and performance status.
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First introduced during the late 1800s, radiation therapy is fundamental to the treatment of cancer. In developed countries, approximately 60% of all patients receive radiation therapy (also known as the sixty percenters), which makes radioresistance in cancer an important and, to date, unsolved, clinical problem. Unfortunately, the therapeutic refractoriness of solid tumors is the rule not the exception, and the ubiquity of resistance also extends to standard chemotherapy, molecularly targeted therapy and immunotherapy. Based on extrapolation from recent clinical inroads with epigenetic agents to prime refractory tumors for maximum sensitivity to concurrent or subsequent therapies, the radioresistant phenotype is potentially reversible, since aberrant epigenetic mechanisms are critical contributors to the evolution of resistant subpopulations of malignant cells. Within the framework of a syllogism, this review explores the emerging link between epigenetics and the development of radioresistance and makes the case that a strategy of pre- or co-treatment with epigenetic agents has the potential to, not only derepress inappropriately silenced genes, but also increase reactive oxygen species production, resulting in the restoration of radiosensitivity.
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Epigénesis Genética , Neoplasias/radioterapia , Tolerancia a Radiación/genética , Humanos , Neoplasias/genéticaRESUMEN
This study reveals a novel interaction between deoxyhemoglobin, nitrite and the non-toxic compound, RRx-001, to generate supraphysiologic levels of nitric oxide (NO) in blood. We characterize the nitrite reductase activity of deoxyhemoglobin, which in the presence of bound RRx-001 reduces nitrite at a much faster rate, leading to markedly increased NO generation. These data expand on the paradigm that hemoglobin generates NO via nitrite reduction during hypoxia and ischemia when nitric oxide synthase (NOS) function is limited. Here, we demonstrate that RRx-001 greatly enhances NO generation from nitrite reduction. RRx-001 is thus the first example of a functional superagonist for nitrite reductase. We hypothesize that physiologically this reaction releases the potentially cytotoxic effector NO selectively in hypoxic tumor regions. It may be that a binary NO-H2O2 trigger is indirectly responsible for the observed tumoricidal activity of RRx-001 since NO is known to inhibit mitochondrial respiration.
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Antineoplásicos/farmacología , Azetidinas/farmacología , Eritrocitos/efectos de los fármacos , Nitrocompuestos/farmacología , Hipoxia Tumoral/efectos de los fármacos , Eritrocitos/metabolismo , Humanos , Técnicas In Vitro , Óxido Nítrico/agonistas , Óxido Nítrico/biosíntesis , Nitrito Reductasas/metabolismoRESUMEN
Small-cell lung cancer (SCLC), initially exquisitely sensitive to first-line cisplatin/etoposide, invariably relapses and acquires a multidrug chemoresistant phenotype that generally renders retreatment with first-line therapy both futile and counterproductive. This report presents the case of a 77-year-old Caucasian male with extensive-stage refractory SCLC who was restarted on platinum doublets as part of a clinical trial called TRIPLE THREAT (NCT02489903) involving pretreatment with the epi-immunotherapeutic agent RRx-001, and who achieved a partial response after only 4 cycles. The patient had received a platinum drug twice before, in 2009 for a diagnosis of non-small-cell lung cancer (squamous cell carcinoma) and in 2015 for SCLC, suggesting that RRx-001 pretreatment may sensitize or resensitize refractory SCLC patients to first-line chemotherapy.
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Few therapeutic options are available for T790M-negative non-small cell lung cancer (NSCLC) after failure of primary epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and chemotherapy. This report presents the case of a 71-year-old Asian female never smoker with EGFR mutated T790M negative non squamous cell lung cancer (NSCLC) pre-treated with the experimental epi-immunotherapeutic agent, RRx-001, that re-responded to single agent carboplatin after failure of platinum doublets, TKIs, pemetrexed and nivolumab. The management of advanced EGFR mutation-positive NSCLC is briefly reviewed herein and the emerging paradigm of episensitization, which contradicts the long-standing and widely accepted tenet about the immutability of resistance and the futility of therapeutic rechallenge, is introduced as a strategy to avert treatment failure and thereby stave off deterioration and death.
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The therapeutic potential of epi-immunotherapeutic anticancer agent RRx-001 in cancer has been validated with preclinical and clinical studies, since RRx-001 has successfully completed a phase 1 trial and multiple single-agent and combination phase 2 trials with preliminary evidence of promising activity are underway. Previous experimental work has implicated diverse anticancer mechanisms such as oxidative stress, ATP and NADPH depletion, anti-angiogenesis and epigenetic modulation in the overall antitumor effect of RRx-001. The hypothesis of this study was that the RRx-001 red blood cells are the essential and de facto intermediaries responsible for the reprograming of tumor behavior via transfer of their intracellular and membrane contents. To test this hypothesis, and thereby resolve the "black box" incompleteness in the continuity of the mechanism, the fate of red blood cells incubated with RRx-001 was explored in vitro and in vivo both in healthy animals and in tumor-bearing mice. The collective results establish that RRx-001-derivatized red blood cells are the critical "missing links" to explain the specificity and anticancer activity of RRx-001, including its immunomodulatory effects on tumor-associated macrophages. These experimental results delineate a novel erythrocyte-based mechanism without precedent in the annals of oncology and open the door to rational combination strategies with RRx-001 both in cancer therapy and beyond, particularly in disease states that affect red blood cell and vascular function such as malaria, leishmaniasis, sickle-cell disease and hemorrhagic shock.
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Antineoplásicos/farmacología , Azetidinas/farmacología , Eritrocitos/efectos de los fármacos , Neoplasias Experimentales/tratamiento farmacológico , Nitrocompuestos/farmacología , Animales , Modelos Animales de Enfermedad , Macrófagos/inmunología , Ratones , Ratones Endogámicos C57BL , Neoplasias Experimentales/inmunología , Neoplasias Experimentales/patología , Distribución AleatoriaRESUMEN
BACKGROUND: The tumor-specific microregional effects of the anticancer agent RRx-001, a novel epigenetic-based radio/chemosensitizer with nitrogen oxide-donating properties in phase II clinical trials, were investigated with whole tissue section quantitative immunohistological staining in mouse SCCVII and human U87 tumors. RESULTS: SCCVII tumors exhibited regions of intermittent perfusion exemplified by co-localization of vessels with the hypoxia marker pimonidazole commonly occurring throughout the tissue. A moderate increase in perfusion (21 to 28 %) was observed after a bolus dose of the perivascular stain DiOC7(3), however, with the absence of an increase in tissue oxygenation. U87 tumors showed an absence of blood flow over large areas of treated tumors after dosing with RRx-001. However, these areas did not become necrotic and returned to near normal levels after 12 h. No significant change in tumor hypoxia was seen at 90 min or 12 h. For both tumor types, RRx-001 treatment resulted in the loss of perfusion in the large regions of the tumor; however, at the 12-h time point, both tumor types showed an increase in vessel perfusion but no significant decrease in hypoxia. CONCLUSIONS: These data suggest a redistribution of blood flow within the tumor for both tumor types akin to vascular normalization. Differences between the tumors were related to tumor architecture and distribution of alpha-smooth muscle actin (α-SMA). RRx-001 shows promise for short-term blood flow redistribution in tumors with a pericyte- and α-SMA-rich vasculature. Expression of α-SMA in tumor vasculature could therefore be useful for predicting tumor response to RRx-001.
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Antineoplásicos/administración & dosificación , Azetidinas/administración & dosificación , Neoplasias/irrigación sanguínea , Neoplasias/tratamiento farmacológico , Nitrocompuestos/administración & dosificación , Actinas/metabolismo , Animales , Antineoplásicos/farmacología , Azetidinas/farmacología , Hipoxia de la Célula/efectos de los fármacos , Línea Celular Tumoral , Epigénesis Genética , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Ratones , Trasplante de Neoplasias , Neoplasias/metabolismo , Nitrocompuestos/farmacología , Nitroimidazoles/administración & dosificación , Nitroimidazoles/farmacología , Microambiente Tumoral/efectos de los fármacosRESUMEN
The anti-proliferative effects of RRx-001, a novel RONS-mediated immuno-epigenetic and vascular normalizing anticancer agent in Phase 2 clinical trials, are not explainable via a single mechanism. Previous research suggested an association between G6PD inhibition and RRx-001 anticancer activity. The results in this study confirm and extend previous observations that RRx-001 exerts its anti-proliferative effect, at least partially, through interference with glucose 6 phosphate dehydrogenase (G6PD), a key enzyme in the pentose phosphate pathway, responsible for maintaining adequate levels of the major cellular reductant, NADPH. RRx-001 affects glucose and G6PD enzyme activity in three different cancer cell lines namely Hep G2, CACO-2, and HT-29. We observed that in all cancer cell lines tested, RRx-001 induced G6PD inhibition in a concentration dependent fashion. Inhibition of G6PD activity associated with a reduction in ribonucleotide synthesis, glutathione reduction and cell proliferation may represent an important mechanism by which RRx-001 exerts its anticancer effects.
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Antineoplásicos/farmacología , Azetidinas/farmacología , Proliferación Celular/efectos de los fármacos , Glucosafosfato Deshidrogenasa/antagonistas & inhibidores , Nitrocompuestos/farmacología , Vía de Pentosa Fosfato/efectos de los fármacos , Células CACO-2 , Ensayos Clínicos Fase II como Asunto , Glucosa/metabolismo , Glucosafosfato Deshidrogenasa/metabolismo , Células HT29 , Humanos , NADP/metabolismoRESUMEN
This report, based on data from a clinical case, proposes that pulmonary tumor thrombotic microangiopathy, an underdiagnosed cause of pulmonary hypertension and death in patients with adenocarcinoma, is a paraneoplastic syndrome (PNS). Clinicians in general must be alert to the presence or development of PNS that may precede, coincide with, follow, or herald the recurrence or the primary diagnosis of malignancy since early recognition facilitates prompt diagnosis and treatment.
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Neuroendocrine tumors (NETs) are grouped together as a single class on the basis of histologic appearance, immunoreactivity for the neuroendocrine markers chromogranin A and synaptophysin, and potential secretion of hormones, neurotransmitters, neuromodulators and neuropeptides. Nevertheless, despite these common characteristics, NETs differ widely in terms of their natural histories: high-grade NETs are clinically aggressive and, like small cell lung cancer, which they most closely resemble, tend to respond to cisplatin and etoposide. In contrast, low-grade NETs, which as a rule progress and behave indolently, do not. In either case, the treatment strategy, apart from potentially curative surgical resection, is very poorly defined. This report describes the case of a 28-year-old white male with a diagnosis of high-grade NET of undetermined primary site metastatic to the lymph nodes, skin and paraspinal soft tissues, treated with the experimental anticancer agent RRx-001, in the context of a phase II clinical trial called TRIPLE THREAT (NCT02489903); serial sampling of tumor material through repeat biopsies demonstrated an intratumoral inflammatory response, including the amplification of infiltrating T cells, which correlated with clinical and symptomatic benefit. This case suggests that pseudoprogression or RRx-001-induced enlargement of tumor lesions, which has been previously described for several RRx-001-treated patients, is the result of tumoral lymphocyte infiltration.
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RRx-001 is a pan-active, systemically nontoxic epigenetic inhibitor under investigation in advanced non-small cell lung cancer, small-cell lung cancer and high-grade neuroendocrine tumors in a Phase II clinical trial entitled TRIPLE THREAT (NCT02489903), which reexposes patients to previously effective but refractory platinum doublets after treatment with RRx-001. The purpose of this case study is first to report a partial response to carboplatin and etoposide in a patient with small-cell lung cancer pretreated with RRx-001, indicating episensitization or resensitization by epigenetic mechanisms, and second to discuss the literature related to small-cell lung cancer and episensitization.
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BACKGROUND: Kim et al. report two patients with melanoma metastases to the brain that responded to treatment with RRx-001 and whole brain radiotherapy (WBRT) without neurologic or systemic toxicity in the context of a phase I/II clinical trial. RRx-001 is an reactive oxygen and reactive nitrogen species (ROS/RNS)-dependent systemically nontoxic hypoxic cell radiosensitizer with vascular normalizing properties under investigation in patients with various solid tumors including those with brain metastases. SIGNIFICANCE: Metastatic melanoma to the brain is historically associated with poor outcomes and a median survival of 4 to 5 months. WBRT is a mainstay of treatment for patients with multiple brain metastases, but no significant therapeutic advances for these patients have been described in the literature. To date, candidate radiosensitizing agents have failed to demonstrate a survival benefit in patients with brain metastases, and in particular, no agent has demonstrated improved outcome in patients with metastatic melanoma. Kim et al. report two patients with melanoma metastases to the brain that responded to treatment with novel radiosensitizing agent RRx-001 and WBRT without neurologic or systemic toxicity in the context of a phase I/II clinical trial.
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From Adam and Eve, to Darwinism, origin stories attempt to fill in the blanks, connect the dots, and define the turning points that are fundamental to subsequent developments. The purpose of this review is to present the origin story of a one-of-a-kind anticancer agent, RRx-001, which emerged from the aerospace industry as a putative radiosensitizer; not since the dynamite-to-dilator transformation of nitroglycerin in 1878 or the post-World War II explosive-to-elixir conversion of hydralazine, an ingredient in rocket fuel, to an antihypertensive, an antidepressant and an antituberculant, has energetic chemistry been harnessed for therapeutic purposes. This is Part 1 of the radiosensitization story; Parts 2 and 3, which detail the crossover activity of RRx-001 as a chemosensitizer in multiple tumor types and disease states including malaria, hemorrhagic shock and sickle cell anemia, are the subject of future reviews.
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Antineoplásicos/química , Azetidinas/química , Neoplasias/radioterapia , Nitrocompuestos/química , Fármacos Sensibilizantes a Radiaciones/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Azetidinas/farmacología , Azetidinas/uso terapéutico , Hipoxia de la Célula/efectos de los fármacos , Epigénesis Genética , Sustancias Explosivas/química , Humanos , Neoplasias/irrigación sanguínea , Nitrocompuestos/farmacología , Nitrocompuestos/uso terapéutico , Fármacos Sensibilizantes a Radiaciones/farmacología , Fármacos Sensibilizantes a Radiaciones/uso terapéuticoRESUMEN
Like Chinese boxes nesting inside each other, the classification of non-small cell lung cancer (NSCLC) is subdivided into smaller and smaller subtypes on the basis of histological and molecular attributes. The latter characterizes NSCLC by its molecular alterations and the identification of inhibitors that target these cancer-specific "driver" mutations. Despite the initial promise of precision-guided therapies to inhibit a finer and finer array of molecular subcategories, despite even the curative potential of immunotherapeutic checkpoint blockade, in particular, casualties still abound and true clinical success stories are few and far between; the ever-present, if sometimes unmentioned, "elephant in the room", is the acquisition of resistance, which, sooner or later, rears its ugly head to undermine treatment success and shorten survival. Emerging data suggests that epigenetic therapies are able to reprogram the aberrant tumor-associated epigenome and 'tame the beast of resistance', thereby prolonging survival. This article reviews the role of epigenetic dysregulation in NSCLC, explores PFS2 as a possible surrogate endpoint, briefly mentions possible biomarkers and highlights combinatorial treatment epigenetic strategies to "prime" tumors and reverse resistance.
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Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Resistencia a Antineoplásicos/genética , Epigénesis Genética , Neoplasias Pulmonares/tratamiento farmacológico , Anticuerpos Monoclonales/farmacología , Azacitidina/farmacología , Azetidinas/farmacología , Benzamidas/farmacología , Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Islas de CpG , Metilación de ADN , Progresión de la Enfermedad , Histonas/química , Humanos , Hidralazina/farmacología , Inmunoterapia/métodos , Neoplasias Pulmonares/patología , Terapia Molecular Dirigida , Mutación , Recurrencia Local de Neoplasia , Nitrocompuestos/farmacología , Nivolumab , Pronóstico , Piridinas/farmacología , Resultado del Tratamiento , Ácido Valproico/farmacologíaRESUMEN
We present the case of a 49-year-old male with metastatic epidermal growth factor receptor (EGFR) mutation-positive adenocarcinoma of the lung that continues to outlive stage IV diagnosis of non-small cell lung cancer after treatment with RRx-001, an experimental anticancer agent with epigenetic and immunologic activity, in the context of a phase II clinical trial called TRIPLE THREAT. Currently, no adequate treatment options exist for patients with EGFR mutation-positive tumors who have failed a 1st-generation tyrosine kinase inhibitor (erlotinib or gefitinib) treatment and do not develop a resistant mutation. Biopsy of a large pancreatic metastasis after RRx-001 demonstrated extensive necrosis with CD3+ and CD8+ immune cell infiltration that appears to correlate with prolonged survival despite end-stage disease. These results suggest that the mode of action of RRx-001 is related to immune stimulation in addition to epigenetic inhibition.