[18F]FDG PET/CT in the Initial Staging and Restaging of Soft-Tissue or Bone Sarcoma in Patients with Negative or Equivocal Findings for Metastases or Limited Recurrence on Conventional Work-up: Results of a Prospective Multicenter Registry.

The purpose of this study was to determine the impact of [18F]FDG PET/CT on the initial staging, restaging, clinical management, and outcomes of patients with soft-tissue and bone sarcomas. Methods: This single-arm, prospective multicenter registry enrolled 304 patients with 320 [18F]FDG PET/CT scans (November 2018 to October 2021). Eligibility included the initial staging of a grade 2 or higher or ungradable soft-tissue or bone sarcoma, with negative or equivocal findings for nodal or distant metastases on conventional imaging before curative-intent therapy, or restaging of patients with a history of treated sarcoma with a suspicion or confirmation of local recurrence or limited metastatic disease who were being considered for curative-intent or salvage therapy. The presence of local recurrence or metastases on [18F]FDG PET/CT was recorded. Clinical management after [18F]FDG PET/CT compared with pre-[18F]FDG PET/CT planned management and quantitative metabolic tumor parameters (SUVmax, metabolic tumor volume, total lesion glycolysis) were correlated with the outcome data for 171 patients. Results: At the initial staging, [18F]FDG PET/CT detected metastases in 17 of 105 patients (16.2%) with no metastases on conventional work-up and confirmed metastases in 44 of 92 patients (47.8%) with equivocal findings for metastases. At the time of restaging, [18F]FDG PET/CT detected local recurrence in 37 of 123 patients (30.1%) and distant metastases in 71 of 123 patients (57.7%). Overall, the change in treatment intent and treatment type was recorded in 64 of 171 cases (37.4%) and 56 of 171 cases (32.8%), respectively. The presence of metastases on [18F]FDG PET/CT was associated with shorter progression-free survival at the initial staging (P = 0.04) and shorter overall survival at the time of recurrence (P = 0.002). All quantitative metabolic tumor parameters correlated with progression-free survival and overall survival. Conclusion: [18F]FDG PET/CT frequently detects additional sites of disease compared with conventional imaging in patients with sarcomas that were being considered for curative-intent or salvage therapy. This increased detection impacts the clinical management in a third of patients referred for initial staging or presumed limited recurrence after primary therapy. The presence of metastases on [18F]FDG PET/CT is associated with poorer outcomes.

Structural insights into selective small molecule activation of PKG1α.

cGMP-dependent protein kinase I-α (PKG1α) is a target for pulmonary arterial hypertension due to its role in the regulation of smooth muscle function. While most work has focused on regulation of cGMP turnover, we recently described several small molecule tool compounds which were capable of activating PKG1α via a cGMP independent pathway. Selected molecules were crystallized in the presence of PKG1α and were found to bind to an allosteric site proximal to the low-affinity nucleotide binding domain. These molecules act to displace the switch helix and cause activation of PKG1α representing a new mechanism for the activation and control of this critical therapeutic path. The described structures are vital to understanding the function and control of this key regulatory pathway.

A convergent fragment coupling strategy to access quaternary stereogenic centers.

The formation of quaternary stereogenic centers via convergent fragment coupling is a longstanding challenge in organic synthesis. Here, we report a strategy for the formation of quaternary stereogenic centers in polycyclic systems based upon the semi-pinacol reaction. In the key transformation, two fragments of a similar size and complexity are joined by a 1,2-addition of an alkenyl lithium to an epoxy ketone, and the resulting epoxy silyl ether undergoes a semi-pinacol rearrangement catalyzed by N-(trimethylsilyl)bis(trifluoromethanesulfonyl)imide (TMSNTf2) or trimethylsilyl trifluoromethanesulfonate (TMSOTf). Polycyclic scaffolds were generated in high yields and the reaction conditions tolerated a variety of functional groups including esters, silyl ethers, enol ethers, and aryl triflates. This method provides a useful strategy for the synthesis of complex polycyclic natural product-like scaffolds with quaternary stereogenic centers from simplified fragments.

Drugging IGF-1R in cancer: New insights and emerging opportunities.

The insulin-like growth factor (IGF) axis plays important roles in cancer development and metastasis. The type 1 IGF receptor (IGF-1R) is a key member in the IGF axis and has long been recognized for its oncogenic role in multiple cancer lineages. Here we review the occurrence of IGF-1R aberrations and activation mechanisms in cancers, which justify the development of anti-IGF-1R therapies. We describe the therapeutic agents available for IGF-1R inhibition, with focuses on the recent or ongoing pre-clinical and clinical studies. These include antisense oligonucleotide, tyrosine kinase inhibitors and monoclonal antibodies which may be conjugated with cytotoxic drug. Remarkably, simultaneous targeting of IGF-1R and several other oncogenic vulnerabilities has shown early promise, highlighting the potential benefits of combination therapy. Further, we discuss the challenges in targeting IGF-1R so far and new concepts to improve therapeutic efficacy such as blockage of the nuclear translocation of IGF-1R.

AKTIP loss is enriched in ERα-positive breast cancer for tumorigenesis and confers endocrine resistance.

Recurrent deletion of 16q12.2 is observed in luminal breast cancer, yet the causal genomic alterations in this region are largely unknown. In this study, we identify that loss of AKTIP, which is located on 16q12.2, drives tumorigenesis of estrogen receptor alpha (ERα)-positive, but not ERα-negative, breast cancer cells and is associated with poor prognosis of patients with ERα-positive breast cancer. Intriguingly, AKTIP-depleted tumors have increased ERα protein level and activity. Cullin-associated and neddylation-dissociated protein 1 (CAND1), which regulates the cullin-RING E3 ubiquitin ligases, protects ERα from cullin 2-dependent proteasomal degradation. Apart from ERα signaling, AKTIP loss triggers JAK2-STAT3 activation, which provides an alternative survival signal when ERα is inhibited. AKTIP-depleted MCF7 cells and ERα-positive patient-derived organoids are more resistant to ERα antagonists. Importantly, the resistance can be overcome by co-inhibition of JAK2/STAT3. Together, our results highlight the subtype-specific functional consequences of AKTIP loss and provide a mechanistic explanation for the enriched AKTIP copy-number loss in ERα-positive breast cancer.

Optimization and Mechanistic Investigations of Novel Allosteric Activators of PKG1α.

Activation of PKG1α is a compelling strategy for the treatment of cardiovascular diseases. As the main effector of cyclic guanosine monophosphate (cGMP), activation of PKG1α induces smooth muscle relaxation in blood vessels, lowers pulmonary blood pressure, prevents platelet aggregation, and protects against cardiac stress. The development of activators has been mostly limited to cGMP mimetics and synthetic peptides. Described herein is the optimization of a piperidine series of small molecules to yield activators that demonstrate in vitro phosphorylation of vasodilator-stimulated phosphoprotein as well as antiproliferative effects in human pulmonary arterial smooth muscle cells. Hydrogen/deuterium exchange mass spectrometry experiments with the small molecule activators revealed a mechanism of action consistent with cGMP-induced activation, and an X-ray co-crystal structure with a construct encompassing the regulatory domains illustrated a binding mode in an allosteric pocket proximal to the low-affinity cyclic nucleotide-binding domain.

Effect of 18F-DCFPyL PET/CT on the Management of Patients with Recurrent Prostate Cancer: Results of a Prospective Multicenter Registry Trial.

Background The high positivity rate of prostate-specific membrane antigen (PSMA) PET in the setting of biochemical failure (BCF), even when conventional imaging is negative, is promising. Purpose To assess the disease detection rate of PSMA-based PET/CT with fluorine 18-DCFPyL as a radiotracer and the PET-directed management change in men with suspected limited recurrent prostate cancer. Materials and Methods This prospective multicenter registry (Ontario PSMA-PET Registry for Recurrent Prostate Cancer, or PREP) enrolled men with BCF after primary therapy (radical prostatectomy plus or minus salvage radiation therapy or primary radiation therapy) and zero to four disease sites at conventional imaging (CT and bone scintigraphy). The positivity rate of PSMA PET according to serum prostate-specific antigen (PSA) level; frequency of local-egional, oligometastatic, and extensive metastatic recurrence; and rate of change in management after PET findings were recorded. The nonparametric Mood median test was used to assess the association between serum PSA level and change in management. Results A total of 1289 men (median age, 71 years [interquartile range, 65-75 years]) were evaluated. PSMA PET helped detect disease in 841 of 1289 men (65%) and in 615 of 999 men (62%) with negative conventional imaging. The recurrence detection rates according to serum PSA level at enrollment were 38% (160 of 424 men), 63% (107 of 171 men), and 83% (573 of 692 men) for PSA under 0.5 ng/mL, 0.5-1.0 ng/mL, and above 1.0 ng/mL, respectively. At PSMA PET, 399 of 1289 men (31%) had local-regional recurrence, 314 (24%) had oligometastatic disease, and 128 (10%) had extensive metastases. Following PET examination, a change in planned management was recorded in 748 of 1289 men (58%), and in 371 of 1250 men (30%), there was a change in management intent, more commonly from palliative to potentially curative intent (255 of 1289 men [20%]). Conclusion Prostate-specific membrane antigen PET helped detect additional sites of disease compared with conventional imaging in approximately 60% of men with biochemical failure and suspected low-volume metastatic disease, resulting in frequent change in management, including a change from palliative to curative or radical intent therapy in 20% of men. Long-term follow-up is needed to determine whether this impacts disease control. Clinical trial registration no. NCT03718260 © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Civelek in this issue.

Total Syntheses of the C19 Diterpenoid Alkaloids (-)-Talatisamine, (-)-Liljestrandisine, and (-)-Liljestrandinine by a Fragment Coupling Approach.

The C19 diterpenoid alkaloids (C19 DTAs) are a large family of natural products, many of which modulate the activity of ion channels in vivo and are therefore of interest for the study of neurological and cardiovascular diseases. The complex architectures of these molecules continue to challenge the state-of-the art in chemical synthesis, particularly with respect to efficient assembly of their polcyclic ring systems. Here, we report the total syntheses of (-)-talatisamine, (-)-liljestrandisine, and (-)-liljestrandinine, three aconitine-type C19 DTAs, using a fragment coupling strategy. Key to this approach is a 1,2-addition/semipinacol rearrangement sequence which efficiently joins two complex fragments and sets an all-carbon quaternary center.

p85ß alters response to EGFR inhibitor in ovarian cancer through p38 MAPK-mediated regulation of DNA repair.

EGFR signaling promotes ovarian cancer tumorigenesis, and high EGFR expression correlates with poor prognosis. However, EGFR inhibitors alone have demonstrated limited clinical benefit for ovarian cancer patients, owing partly to tumor resistance and the lack of predictive biomarkers. Cotargeting EGFR and the PI3K pathway has been previously shown to yield synergistic antitumor effects in ovarian cancer. Therefore, we reasoned that PI3K may affect cellular response to EGFR inhibition. In this study, we revealed PI3K isoform-specific effects on the sensitivity of ovarian cancer cells to the EGFR inhibitor erlotinib. Gene silencing of PIK3CA (p110α) and PIK3CB (p110ß) rendered cells more susceptible to erlotinib. In contrast, low expression of PIK3R2 (p85ß) was associated with erlotinib resistance. Depletion of PIK3R2, but not PIK3CA or PIK3CB, led to increased DNA damage and reduced level of the nonhomologous end joining DNA repair protein BRD4. Intriguingly, these defects in DNA repair were reversed upon erlotinib treatment, which caused activation and nuclear import of p38 MAPK to promote DNA repair with increased protein levels of 53BP1 and BRD4 and foci formation of 53BP1. Remarkably, inhibition of p38 MAPK or BRD4 re-sensitized PIK3R2-depleted cells to erlotinib. Collectively, these data suggest that p38 MAPK activation and the subsequent DNA repair serve as a resistance mechanism to EGFR inhibitor. Combined inhibition of EGFR and p38 MAPK or DNA repair may maximize the therapeutic potential of EGFR inhibitor in ovarian cancer.

Strategic Combination Therapies for Ovarian Cancer.

Ovarian cancer remains the leading cause of gynecologic cancer-related deaths among women worldwide. The dismal survival rate is partially due to recurrence after standardized debulking surgery and first-line chemotherapy. In recent years, targeted therapies, including antiangiogenic agents or poly (ADP-ribose) polymerase inhibitors, represent breakthroughs in the treatment of ovarian cancer. As more therapeutic agents become available supplemented by a deeper understanding of ovarian cancer biology, a range of combination treatment approaches are being actively investigated to further improve the clinical outcomes of the disease. These combinations, which involve DNA-damaging agents, targeted therapies of signaling pathways and immunotherapies, simultaneously target multiple cancer pathways or hallmarks to induce additive or synergistic antitumor activities. Here we review the preclinical data and ongoing clinical trials for developing effective combination therapies in treating ovarian cancer. These emerging therapeutic modalities may reshape the treatment landscape of the disease.

p85ß regulates autophagic degradation of AXL to activate oncogenic signaling.

PIK3R2 encodes the p85ß regulatory subunit of phosphatidylinositol 3-kinase and is frequently amplified in cancers. The signaling mechanism and therapeutic implication of p85ß are poorly understood. Here we report that p85ß upregulates the protein level of the receptor tyrosine kinase AXL to induce oncogenic signaling in ovarian cancer. p85ß activates p110 activity and AKT-independent PDK1/SGK3 signaling to promote tumorigenic phenotypes, which are all abolished upon inhibition of AXL. At the molecular level, p85ß alters the phosphorylation of TRIM2 (an E3 ligase) and optineurin (an autophagy receptor), which mediate the selective regulation of AXL by p85ß, thereby disrupting the autophagic degradation of the AXL protein. Therapeutically, p85ß expression renders ovarian cancer cells vulnerable to inhibitors of AXL, p110, or PDK1. Conversely, p85ß-depleted cells are less sensitive to these inhibitors. Together, our findings provide a rationale for pharmacological blockade of the AXL signaling axis in PIK3R2-amplified ovarian cancer.

Deregulated Gab2 phosphorylation mediates aberrant AKT and STAT3 signaling upon PIK3R1 loss in ovarian cancer.

Copy number loss of PIK3R1 (p85α) most commonly occurs in ovarian cancer among all cancer types. Here we report that ovarian cancer cells manifest a spectrum of tumorigenic phenotypes upon knockdown of PIK3R1. PIK3R1 loss activates AKT and p110-independent JAK2/STAT3 signaling through inducing changes in the phosphorylation of the docking protein Gab2, thereby relieving the negative inhibition on AKT and promoting the assembly of JAK2/STAT3 signalosome, respectively. Additional mechanisms leading to AKT activation include enhanced p110α kinase activity and a decrease in PTEN level. PIK3R1 loss renders ovarian cancer cells vulnerable to inhibition of AKT or JAK2/STAT3. The combination of AKT and STAT3 inhibitors significantly increases the anti-tumor effect compared to single-agent treatments. Together, our findings provide a rationale for mechanism-based therapeutic approach that targets tumors with loss of PIK3R1.

Effect of PET/CT on the Management and Outcomes of Participants with Hodgkin and Aggressive Non-Hodgkin Lymphoma: A Multicenter Registry.

Purpose To determine the relationship of PET/CT staging to the management and outcomes of participants with apparent limited-stage (LS) Hodgkin lymphoma (HL) or aggressive non-HL (ANHL) treated with curative intent. Materials and Methods This prospective multicenter registry included 850 participants (467 men and 383 women; median age, 54.1 years) from nine centers who had LS HL or ANHL on the basis of clinical data and CT, or with equivocal CT for advanced stage, who were considered for curative-intent first-line therapy. Participants were recruited between May 1, 2013, and December 31, 2015. Pre-PET/CT treatment plan was compared with treatment provided. Survival and second-line therapy initiation were compared with an historical control pool staged by using CT alone. Administrative data sources were used to control for baseline characteristics. Outcomes were assessed by using adjusted Cox proportional hazards regression and propensity score matching. Results PET/CT helped to upstage 150 of 850 participants (17.6%). There was a change in planned therapy in 224 of 580 (38.6%) of participants after PET/CT. There was a lower 1-year mortality for participants with ANHL in the PET/CT versus CT cohort (hazard ratio, 0.63; 95% confidence interval: 0.40, 1.0; P < .05) and for those with LS at PET/CT compared with those with LS at CT (hazard ratio, 0.40; 95% confidence interval: 0.21, 0.74; P = .004). For participants with HL, no 1-year outcome difference was found (P = .16). Conclusion PET/CT helped to upstage approximately 18% of participants and planned management was frequently altered. Participants with aggressive non-Hodgkin lymphoma whose first-line therapy was guided by PET/CT had significantly better survival compared with participants whose treatment was guided by CT. © RSNA, 2018 Online supplemental material is available for this article. See also the editorial by Scott in this issue.

[18 F]-FDG PET/CT in the staging and management of indolent lymphoma: A prospective multicenter PET registry study.

BACKGROUND: To measure the clinical impact of pretreatment fludeoxyglucose positron emission tomography/computed tomography (PET/CT) on the staging and management of apparent limited stage indolent lymphoma being considered for curative radiation therapy. METHODS: We conducted a prospective multicenter registry study that included 197 patients accrued between May 1, 2012, and December 31, 2015. Pre-PET/CT stage, determined by clinical and CT data, was documented. If pre-PET/CT stage was indeterminate, a stage was assigned to the patient by the referring oncologist according to best clinical judgment and treatment intent. After PET/CT, revised stage and planned management were recorded and compared with data on actual treatment received available through provincial databases (n = 155). RESULTS: PET/CT resulted in the upstaging of 47 (23.9%) patients with presumed limited stage disease (stage I-II) to advanced stage disease (stage III-IV) (P < .0001). Ten (5.1%) patients were downstaged by PET/CT, 4 of whom migrated from advanced to limited stage disease. Twenty-eight (14.2%) patients with a specific pre-PET/CT stage had equivocal PET/CT findings that required further evaluation to confirm disease extent. After PET/CT, 95 (61.3%) patients were planned to receive active treatment. Of the 59 patients planned for radiotherapy alone post-PET/CT, 34 (57.6%) received this treatment (P = .002), and nearly 80% of them (n = 27) had confirmed limited stage disease. CONCLUSION: PET/CT has a significant impact on staging and management in patients with apparent limited stage indolent lymphoma who are being considered for curative radiotherapy. PET/CT should be routinely incorporated into the workup of these patients. Cancer 2017;123:2860-66. © 2017 American Cancer Society.

The primary care physician's role in the monitoring and management of the potential sequelae of the medical treatment of prostate cancer: early and late.

Significant progress has been made in the management of aggressive prostate cancer. The established old and new treatments have resulted in the significant delay in progression of disease, improvement of the quality of life, as well as the increase in the overall survival of men with advanced prostate cancer. However, these therapies carry with them possible adverse effects that primary care physicians are experienced in managing. Thus, there is an increasing need for the urologist to involve and partner closely with the primary care practitioner to prevent, identify and manage the potential side effects of these life-changing therapies.

FBI-1 Is Overexpressed in Gestational Trophoblastic Disease and Promotes Tumor Growth and Cell Aggressiveness of Choriocarcinoma via PI3K/Akt Signaling.

Human placental trophoblasts can be considered pseudomalignant, with tightly controlled proliferation, apoptosis, and invasiveness. Gestational trophoblastic disease (GTD) represents a family of heterogeneous trophoblastic lesions with aberrant apoptotic and proliferative activities and dysregulation of cell signaling pathways. We characterize the oncogenic effects of factor that binds to the inducer of short transcripts of HIV-1 [FBI-1, alias POZ and Krüppel erythroid myeloid ontogenic factor (POKEMON)/ZBTB7A] in GTD and its role in promoting cell aggressiveness in vitro and tumor growth in vivo. IHC studies showed increased nuclear expression of FBI-1, including hydatidiform moles, choriocarcinoma (CCA), and placental site trophoblastic tumor, in GTD. In JAR and JEG-3 CCA cells, ectopic FBI-1 expression opposed apoptosis through repression of proapoptotic genes (eg, BAK1, FAS, and CASP8). FBI-1 overexpression also promoted Akt activation, as indicated by Akt-pS473 phosphorylation. FBI-1 overexpression promoted mobility and invasiveness of JEG-3 and JAR, but not in the presence of the phosphoinositide 3-kinase inhibitor LY294002. These findings suggest that FBI-1 could promote cell migration and invasion via phosphoinositide 3-kinase/Akt signaling. In vivo, nude mice injected with CCA cells with stable FBI-1 knockdown demonstrated reduced tumor growth compared with that in control groups. These findings suggest that FBI-1 is clinically associated with the progression of, and may be a therapeutic target in, GTD, owing to its diverse oncogenic effects on dysregulated trophoblasts.

A unified strategy to ent-kauranoid natural products: total syntheses of (-)-trichorabdal A and (-)-longikaurin E.

The first total syntheses of (-)-trichorabdal A and (-)-longikaurin E are reported. A unified synthetic strategy is employed that relies on a Pd-mediated oxidative cyclization of a silyl ketene acetal to generate an all-carbon quaternary center and build the bicyclo[3.2.1]octane framework. These studies, taken together with our previous synthesis of (-)-maoecrystal Z, demonstrate that three architecturally distinct ent-kauranoids can be prepared from a common spirolactone intermediate.