Harry Lybeck

RRx-001 in Refractory Small-Cell Lung Carcinoma: A Case Report of a Partial Response after a Third Reintroduction of Platinum Doublets

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.

A Review of Two Promising Radiosensitizers in Brain Metastases: Rrx-001 and 2-Deoxyglucose

The origin of the common phrase “your name is mud” may derive from the ordeal of 19th century physician, Dr. Samuel Mudd, who was perhaps wrongly convicted of conspiracy in the assassination of President Abraham Lincoln. Mudd’s crime may have only been bad luck: Lincoln’s assassin, John Wilkes Booth, allegedly previously unknown to the doctor, had broken his leg and happened across Mudd who, unwisely, as it turned out, set the fracture, and his own subsequent fate, which included life imprisonment with hard labor, making him a potential victim of circumstance rather than the perpetrator of a crime. Mudd’s grandson, also a physician, tried unsuccessfully to clear his grandfather’s widely reviled name, which as a result has remained, both literally and figuratively, Mudd. This historical analogy highlights the important point that radiosensitizers as a class have been ignored rather than adored due to their failed reputation. Hence, in the field of radiation oncology, the “your name is mud” expression applies to radiation sensitizers, which from hyperbaric oxygen and the nitroimidazoles, to motexafin gadolinium, tirapazamine and efaproxiral have generally overpromised and under delivered with respect to survival treatment benefits in multiple different indications. However, newer non-toxic radiosensitizers on the horizon such as the antienergetic epigenetic redox modulator, RRx-001, that will start a Phase 2 clinical trial with concurrent whole brain radiotherapy (WBRT) in subjects with brain metastases, may finally validate the underlying promise and unrealized potential of these agents. The successful treatment of brain metastases is at least a four-hurdle process involving penetration, retention, selectivity and toxicity. This article will review the mechanism of the radiosensitizers, RRx- 001, and 2-deoxyglucose, as examples or “role models” for therapies that theoretically are able to overcome these substantial in vivo obstacles to successfully treat brain metastases. It is the thesis of this review that new radiosensitizers are urgently needed and their poor reputation should be overcome.

The Effect of Pertinent and Non-Pertinent Stimuli on the Secretions of Thyrotropin and Corticotropin

The authors wished to test the extent to which TSH, ACTH or both, are secreted by pituitary cells during the stress of acute exposure to cold. Differences in secretion were found between rat and rabbit.

No patient left behind: The promise of immune priming with epigenetic agents

ABSTRACT 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).

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

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.

Pulmonary Tumor Thrombotic Microangiopathy: A New Paraneoplastic Syndrome?

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.

RRx-001 Priming of PD-1 Inhibition in the Treatment of Small Cell Carcinoma of the Vagina: A Rare Gynecological Tumor

Small cell carcinoma of the vagina is rare, so rare in fact that the total number reported in English-language journals is less than 30. Due to this extremely low incidence, no specific treatment guidelines have been established, and most of what is clinically known is derived from a handful of single case reports. However, as befitting its highly aggressive histologic features, which are reminiscent of small cell lung cancer (SCLC), first-line treatment is modeled after SCLC. Herein is reported the case of a 51-year-old African-American patient with metastatic biopsy-proven small cell carcinoma of the vagina that progressed through multiple therapies: first-line cisplatin and etoposide (making it platinum-resistant) and radiotherapy, followed by the tumor macrophage-stimulating agent RRx-001 in a clinical trial called QUADRUPLE THREAT, which per protocol preceded a mandated rechallenge with cisplatin and etoposide. RECIST v.1.1 tumor progression on both RRx-001 and cisplatin/etoposide was accompanied by central necrosis in several of the enlarged lymph nodes and hepatic metastases, which may have been evidence of pseudoprogression, accounting for her ongoing longer-than-expected survival, since the necrotic tissue may have primed the activity of the PD-1 inhibitor. The lack of response to RRx-001 is hypothesized to have correlated with sparse tumor macrophage infiltration, seen on pre- and post-treatment biopsies, since the mechanism of action of RRx-001 relates to stimulation of tumor-associated macrophages.

Turning on the Radio: Epigenetic Inhibitors as Potential Radiopriming Agents

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.