Proteogenomic analysis of lung adenocarcinoma reveals tumor heterogeneity, survival determinants, and therapeutically relevant pathways.

We present a deep proteogenomic profiling study of 87 lung adenocarcinoma (LUAD) tumors from the United States, integrating whole-genome sequencing, transcriptome sequencing, proteomics and phosphoproteomics by mass spectrometry, and reverse-phase protein arrays. We identify three subtypes from somatic genome signature analysis, including a transition-high subtype enriched with never smokers, a transversion-high subtype enriched with current smokers, and a structurally altered subtype enriched with former smokers, TP53 alterations, and genome-wide structural alterations. We show that within-tumor correlations of RNA and protein expression associate with tumor purity and immune cell profiles. We detect and independently validate expression signatures of RNA and protein that predict patient survival. Additionally, among co-measured genes, we found that protein expression is more often associated with patient survival than RNA. Finally, integrative analysis characterizes three expression subtypes with divergent mutations, proteomic regulatory networks, and therapeutic vulnerabilities. This proteogenomic characterization provides a foundation for molecularly informed medicine in LUAD.

Approach to Pancytopenia in a Deployed Service Member.

Background: Pancytopenia is a result of increased destruction or decreased production of bone marrow cells and has a broad differential. Pernicious anemia commonly presents as a macrocytic anemia and is typically autoimmune in nature and the result of vitamin B12 deficiency. Pancytopenia is a rare presentation of this disorder especially in the setting of hemolysis. Testing in the deployed setting may be limited and/or challenging. Case Presentation: A 24-year-old female patient with a history of Hashimoto thyroiditis presented during an overseas deployment with a witnessed syncopal episode and was found to be pancytopenic with a mild transaminitis and laboratory tests demonstrating hemolysis. Though initially she was hypotensive, tachycardic, and febrile, her vitals improved after multiple transfusions, but she had persistent cytopenia with transfusion dependence, concerning for aplastic anemia or acute leukemia. Conclusions: Testing for B12 deficiency is crucial in symptomatic, patients with pancytopenic to either diagnose or exclude pernicious anemia and conserve resources by preventing costly workup and transfer/escalation of medical care, especially in the deployed setting. A predeployment screening in those with history of autoimmune disorders may be warranted.

RRx-001 followed by platinum plus etoposide in patients with previously treated small-cell lung cancer.

BACKGROUND: This exploratory single-arm phase II study evaluated the efficacy and safety of RRx-001 followed by reintroduction of platinum plus etoposide in patients with previously treated small-cell lung cancer (SCLC). METHODS: Patients were treated with RRx-001 4 mg IV on day 1 of each week of a 21-day cycle followed at progression by re-challenge with etoposide 80-100 IV mg/m2 on days 1, 2 and 3 and cisplatin 60-80 mg/m2 IV on day 1 or carboplatin AUC 5-6 IV on day 1, every 21 days. The primary end points were overall survival (OS) and overall response rate to platinum regimen. RESULTS: Twenty-six patients were enroled and received at least one dose of RRx-001. The median number of prior lines of therapy was 2 (range 1-9) and 19 (73.1%) patients had platinum-resistant disease. In the intention-to-treat population, one patient (3.8%) had complete response and six (23.1%) had partial response on platinum plus etoposide. The estimated median and 12-month OS from enrolment were 8.6 months and 44.1%, respectively. The most common treatment-emergent adverse event from RRx-001 was mild discomfort at the infusion site (23%). CONCLUSIONS: RRx-001 followed by re-challenge with platinum plus etoposide chemotherapy is feasible and associated with promising results. CLINICAL TRIAL REGISTRATION: NCT02489903.

Complete metabolic response of metastatic castration-resistant neuroendocrine carcinoma of the prostate after treatment with RRx-001 and reintroduced platinum doublets.

Presented herein is the case of a heavily pretreated patient with high-grade neuroendocrine prostate cancer that achieved a complete metabolic response on platinum-based chemotherapy after treatment with the dual CD-47 and SIRP-α inhibitor, RRx-001, in a Phase II clinical trial.

Superior Vena Cava Syndrome in a Patient with Small-Cell Lung Cancer: A Case Report.

Superior vena cava (SVC) syndrome, a potential oncologic emergency, is closely associated with malignancy and right-sided lung cancer in particular. A case of SVC syndrome presenting with facial swelling, neck distension, and enlarged veins of the upper chest, which developed over a period of 5 weeks in a 46-year-old patient on a clinical trial with small-cell lung cancer, is reported. Computed tomography scan of the chest revealed slight enlargement of a superior conglomerate mediastinal lymphadenopathy and intramural thrombus of the SVC. The etiology, diagnosis, and treatment of the SVC syndrome are discussed.

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.

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.

Addressing the elephant in the room, therapeutic resistance in non-small cell lung cancer, with epigenetic therapies.

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.