RRx-001-Induced Tumor Necrosis and Immune Cell Infiltration in an EGFR Mutation-Positive NSCLC with Resistance to EGFR Tyrosine Kinase Inhibitors: A Case Report

Brzezniak, Christina; Schmitz, Bruno A.; Peterson, Paul; Degesys, Aiste; Oronsky, Bryan; Scicinski, Jan; Caroen, Scott; Carter, Corey A.

doi:10.1159/000443605

Cited by 13 publications

(11 citation statements)

References 18 publications

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“…Xmrk is a fish oncogene and is basically a mutated form of EGFR with hyperactivity 31 . In human HCC patients, EGFR mutations also cause increased tumor infiltration of immune cells and necrosis 32 . Thus, both oncogenes studied in the present report are actively involved in stromal cell activities in human tumors.…”

Section: Discussionmentioning

confidence: 99%

Activation of liver stromal cells is associated with male-biased liver tumor initiation in xmrk and Myc transgenic zebrafish

Yang

Bai

Gong

2017

Sci Rep

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Hepatocellular carcinoma (HCC) is more prevalent in men than in women. Previously we have found that some stromal cells, including hepatic stellate cells (HSCs), neutrophils and macrophages, play crucial roles in promoting sex disparity in kras V12-induced zebrafish HCC. The activation of HSCs is mediated by serotonin while activation of neutrophils and macrophages is mediated by cortisol. To ensure that these findings are also applicable to other oncogene induced tumors, stromal cell activation was compared between male and female fish during liver tumorigenesis initiated by xmrk or Myc oncogene. Consistently, we observed male-biased liver tumorigenesis in the xmrk and Myc models. In both models, there was a higher rate of HSC activation accompanied with a higher level of serotonin in male liver tumors. For tumor-infiltrated neutrophils and macrophages, significantly higher densities in male liver tumors were observed in both xmrk and Myc models. However, the male-biased increase of cortisol was observed only in xmrk- but not apparently in Myc expressing liver tumors. Overall, these observations are consistent with the observations in the kras liver tumor model, indicating that the serotonin- and cortisol-mediated pathways also play roles in sex disparity of liver tumors caused by other molecular pathways.

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Section: Discussionmentioning

confidence: 99%

Activation of liver stromal cells is associated with male-biased liver tumor initiation in xmrk and Myc transgenic zebrafish

Yang

Bai

Gong

2017

Sci Rep

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“…In the present report, a follow-up to a recently published case report in this journal [ 15 ], which details dramatic RRx-001-induced intratumoral necrosis and immune infiltration in an EGFR-mutated NSCLC patient, evidence of subsequent episensitization to platinum doublets in the form of a partial response is described.…”

Section: Introductionmentioning

confidence: 61%

Partial Response to Platinum Doublets in Refractory EGFR-Positive Non-Small Cell Lung Cancer Patients after RRx-001: Evidence of Episensitization

Carter¹,

Oronsky²,

Caroen³

et al. 2016

Case Rep Oncol

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RRx-001, an experimental systemically non-toxic epi-immunotherapeutic agent, which potentiates the resensitization of resistant cancer cells to formerly effective therapies, is under active investigation in several clinical trials that are based on sequential or concomitant rechallenge to resistant first- or second-line regimens. One of these trials is designated TRIPLE THREAT (NCT02489903), because it explores the conditioning or priming effect of RRx-001 on three tumor types - non-small cell lung cancer (NSCLC), small cell lung cancer and high-grade neuroendocrine tumors - prior to re-administration of platinum doublets. In follow-up to a recent case study, which describes early monotherapeutic benefit with RRx-001 in a refractory EGFR-mutated NSCLC tumor, we present subsequent evidence of a radiological partial response to reintroduced platinum doublets after RRx-001. For the 50% of patients with EGFR-mutated NSCLC who progress on EGFR-tyrosine kinase inhibitors (without evidence of a T790M mutations) as well as platinum doublets and pemetrexed/taxane, no other clinically established treatment options exist. A retrial of these therapies in EGFR-positive NSCLC patients via priming with epigenetic agents such as RRx-001 constitutes a strategy to ‘episensitize' tumors (i.e. reverse resistance by epigenetic means) and to extend overall survival.

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“…Recently published case reports of partial responses in NSCLC13,28 in the QUADRUPLE THREAT trial raise the possibility that RRx-001 may broadly alter the multidrug resistance phenotype, sensitizing or resensitizing heavily pretreated patients with platinum-based resistance in other non-thoracic tumor types where doublet regimens are approved or considered the mainstay of care, such as gastroesophageal, transitional cell and bladder cancer, cervical, testicular, and head and neck cancers. Additional studies are needed in support of this hypothesis and early observations.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, serial tumor biopsies have demonstrated that RRx-001 initiates an immunologically driven inflammatory and edematous response 9,13 and not uncommonly misinterpreted as tumor progression on 6- or 8-week scans, 14 which is potentially a further justification for sequential dosing of RRx-001 followed by chemotherapy, since it may take up to 12 weeks to resolve the inflammation and edema and to shrink or stabilize the tumor.…”

Section: Introductionmentioning

confidence: 99%

A Partial Response to Reintroduced Chemotherapy in a Resistant Small Cell Lung Cancer Patient after Priming with RRx-001

Oronsky¹,

Caroen²,

Zeman

et al. 2016

Clin Med Insights Oncol

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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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RRx-001-Induced Tumor Necrosis and Immune Cell Infiltration in an EGFR Mutation-Positive NSCLC with Resistance to EGFR Tyrosine Kinase Inhibitors: A Case Report

Cited by 13 publications

References 18 publications

Activation of liver stromal cells is associated with male-biased liver tumor initiation in xmrk and Myc transgenic zebrafish

Activation of liver stromal cells is associated with male-biased liver tumor initiation in xmrk and Myc transgenic zebrafish

Partial Response to Platinum Doublets in Refractory EGFR-Positive Non-Small Cell Lung Cancer Patients after RRx-001: Evidence of Episensitization

A Partial Response to Reintroduced Chemotherapy in a Resistant Small Cell Lung Cancer Patient after Priming with RRx-001

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