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 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.

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.

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.

The Case of a Zebra That Was Misdiagnosed as a Horse: Pulmonary Tumor Thrombotic Microangiopathy, a New Paraneoplastic Syndrome, Mimicking PD-1-Induced Pneumonitis.

A case report of a 47-year-old woman with triple-negative breast cancer on a clinical trial called PRIMETIME (NCT02518958) who received the anti-PD-1 inhibitor nivolumab and the experimental anticancer agent RRx-001 is presented. Although initially diagnosed and treated for anti-PD-1-induced pneumonitis, clinical and radiological abnormalities triggered further investigation, leading to the diagnosis of pulmonary tumor thrombotic microangiopathy (PTTM). This example highlights the importance of exercising due diligence in determining immune-related adverse events and suggests that PD-1-induced pneumonitis should be a diagnosis of exclusion rather than a diagnosis by default. A case history and review of the literature are presented for PTTM, which we propose to define as a paraneoplastic syndrome.

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

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.

Episensitization: Defying Time's Arrow.

The development of cancer is driven by complex genetic and epigenetic changes that result in aberrant and uncontrolled cellular growth. Epigenetic changes, in particular, are implicated in the silencing or activation of key genes that control cellular growth and apoptosis and contribute to transformative potential. The purpose of this review is to define and assess the treatment strategy of "episensitization," or the ability to sensitize cancer cells to subsequent therapy by resetting the epigenetic infrastructure of the tumor. One important facet is resensitization by epigenetic mechanisms, which goes against the norm, i.e., challenges the long-held doctrine in oncology that the reuse of previously tried and failed therapies is a clinically pointless endeavor. Thus, episensitization is a hybrid term, which covers recent clinically relevant observations and refers to the epigenomic mechanism of resensitization. Among the many formidable challenges in the treatment of cancer, the most inevitable is the development of acquired therapeutic resistance. Here, we present the basic principles behind episensitization and highlight the evidence suggesting that epigenetically mediated histone hypoacetylation and DNA hypermethylation events may reverse clinical drug resistance. The potential reversibility of epigenetic changes and the microenvironmental impact of epigenetic control on gene expression may mediate a return to a baseline state of treatment susceptibility. Episensitization is a novel and highly practical management strategy both to prevent the practice of permanent treatment discontinuation with the occurrence of resistance, which rapidly exhausts remaining options in the pharmaceutical armamentarium and to significantly extend patient survival. Accordingly, this review highlights several epigenetic agents including decitabine, vorinostat, entinostat, 5-azacitidine, oncolytic viruses, and RRx-001.

Follow the ATP: tumor energy production: a perspective.

As early as the 1920s, the eminent physician and chemist, Otto Warburg, nominated for a second Nobel Prize for his work on fermentation, observed that the core metabolic signature of cancer cells is a high glycolytic flux. Warburg averred that the prime mover of cancer is defective mitochondrial respiration, which drives a switch to an alternative energy source, aerobic glycolysis in lieu of Oxidative Phosphorylation (OXPHOS), in an attempt to maintain cellular viability and support critical macromolecular needs. The cell, deprived of mitochondrial ATP production, must reprogram its metabolism as a secondary survival mechanism to maintain sufficient ATP and NADH levels for macromolecule production, membrane integrity and DNA synthesis as well as maintenance of membrane ionic gradients. A time-tested method to identify and disrupt criminal activity is to "follow the money" since the illicit proceeds from crime are required to underwrite it. By analogy, strategies to target cancer involve following and disrupting the flow of ATP and NADH, the energetic and redox "currencies" of the cell, respectively, since the tumor requires high levels of ATP and NADH, not only for metastasis and proliferation, but also, on a more basic level, for survival. Accordingly, four broad ATP reduction strategies to impact and potentially derail cancer energy production are highlighted herein: 1) small molecule energy-restriction mimetic agents (ERMAs) that target various aspects of energy metabolism, 2) reduction of energy 'subsidization' with autophagy inhibitors, 3) acceleration of ATP turnover to increase energy inefficiency, and 4) dietary energy restriction to limit the energy supply.

The scarlet letter of alkylation: a mini review of selective alkylating agents.

If there were a stigma scale for chemotherapy, alkylating agents would be ranked at the top of the list. The chemical term alkylation is associated with nonselective toxicity, an association that dates back to the use of nitrogen mustards during World War I as chemical warfare agents. That this stigma persists and extends to compounds that, through selectivity, attempt to "tame" the indiscriminate destructive potential of alkylation is the subject of this review. Selective alkylation, as it is referred to herein, constitutes an extremely nascent and dynamic field in oncology. The pharmacodynamic response to this selective strategy depends on a delicate kinetic balance between specificity and the rate and extent of binding. Three representative compounds are presented: RRx-001, 3-bromopyruvate, and TH-302. The main impetus for the development of these compounds has been the avoidance of the serious complications of traditional alkylating agents; therefore, it is the thesis of this review that they should not experience stigma by association.

Beyond antiangiogenesis: vascular modulation as an anticancer therapy-a review.

This review attempts to move beyond the traditional borders of antiangiogenesis and toward the dynamic, evolving strategies of vascular modulation. This repositioning entails a two-fold paradigm shift: conceptually, to a view of antiangiogenesis as only one part of a larger story, and therapeutically, to approaches which attempt to modulate tumor blood flow instead of simply inhibiting it. Three vascular modulation strategies-provascular, antivascular, and redistributive-are presented with representative compounds. These vascular modulation strategies are described in specific measurable characteristics (blood vessel maturity and type, effect on blood flow, microenvironmental target, molecular target, angiogenic biomarker, and imaging biomarkers) that will help define the tumor types that are more susceptible to a particular vascular modulation strategy thereby guiding therapeutic agent selection and enabling a personalized medicine approach.

Is Nitric Oxide (NO) the Last Word in Radiosensitization? A Review.

As a short-lived radical that diffuses across membranes, rather than interacting with membrane-bound receptors, nitric oxide (NO) represents a significant departure from synthetically derived radiosensitizers. An endogenous compound, NO may equal or surpass its molecular cousin, oxygen, as a hypoxic radiosensitizer, through pleiotropic phenotypic effects on tumor perfusion, cell signaling, mitochondrial respiration, the fixation of radiation-induced damage, and the radioprotection of normal tissue. However, unlike oxygen, in the context of radiosensitization, the clinical role and utility of NO are poorly understood, with often contradictory and controversial reported effects: whether NO functions as a radiosensitizer may ultimately be contextual to the tumor microenvironment. This may make NO manipulation an ideal candidate for a personalized radiosensitization approach tailored to specific patient and tumor types/microenvironmental characteristics. Effective delivery of NO both systemically and directly to the tumor may be critical to the success of this approach. Compounds that release NO or NO precursors have the potential to drive innovation and result in a new fertile branch of the radiosensitizer tree.

Light-fluorous safety-catch arylgermanes - exceptionally robust, photochemically activated precursors for biaryl synthesis by Pd(0) catalysed cross-coupling.

A new class of arylgermane derivative that participate efficiently in Pd(0)-catalysed cross-coupling reactions with aryl bromides following photochemical activation is described.

Development of an indole safety-catch linker using analytical constructs.

The development, evaluation, and application of a novel safety-catch linker for solid-phase synthesis based on an N-tosylindole is reported. The development of this linker using analytical constructs to aid analysis is discussed.

Analytical techniques for small molecule solid phase synthesis.

Although resin-based chemistry offers many practical advantages over conventional solution phase for the synthesis of combinatorial libraries, effective monitoring of reactions conducted on the support remains a challenge. A number of techniques have been developed to enable the analysis of solid phase organic synthesis either by monitoring the resin-bound species directly or by the analysis of small quantities of material cleaved from the support. This review outlines some of the principles of the various techniques for the analysis of intermediates and products obtained from solid-phase chemistry.

Analytical construct resins for analysis of solid-phase chemistry.

Rapid and unambiguous analysis of reactions performed on resin supports can be achieved by using "analytical constructs". These resins allow the synthesis of materials using solid-phase methods in the usual manner, but they also contain functionality enabling cleavage of analytically enhanced derivatives of the resin-bound products. This is possible due to the use of two linkers bound in series to the polymer. Cleavage at the first linker yields the products attached to an analytical enhancer that facilitates detection. Orthogonal cleavage at the second linker yields the desired products in the usual manner.