Gazala N. Khan

A Phase I/II Trial of Intensity Modulated Radiation (IMRT) Dose Escalation With Concurrent Fixed-dose Rate Gemcitabine (FDR-G) in Patients With Unresectable Pancreatic Cancer

PURPOSE Local failure in unresectable pancreatic cancer may contribute to death. We hypothesized that intensification of local therapy would improve local control and survival. The objectives were to determine the maximum tolerated radiation dose delivered by intensity modulated radiation with fixed-dose rate gemcitabine (FDR-G), freedom from local progression (FFLP), and overall survival (OS). METHODS AND MATERIALS Eligibility included pathologic confirmation of adenocarcinoma, radiographically unresectable, performance status of 0-2, absolute neutrophil count of ≥ 1,500/mm(3), platelets ≥ 100,000/mm(3), creatinine <2 mg/dL, bilirubin <3 mg/dL, and alanine aminotransferase/aspartate aminotransferase ≤ 2.5 × upper limit of normal. FDR-G (1000 mg/m(2)/100 min intravenously) was given on days -22 and -15, 1, 8, 22, and 29. Intensity modulated radiation started on day 1. Dose levels were escalated from 50-60 Gy in 25 fractions. Dose-limiting toxicity was defined as gastrointestinal toxicity grade (G) ≥ 3, neutropenic fever, or deterioration in performance status to ≥ 3 between day 1 and 126. Dose level was assigned using TITE-CRM (Time-to-Event Continual Reassessment Method) with the target dose-limiting toxicity (DLT) rate set to 0.25. RESULTS Fifty patients were accrued. DLTs were observed in 11 patients: G3/4 anorexia, nausea, vomiting, and/or dehydration (7); duodenal bleed (3); duodenal perforation (1). The recommended dose is 55 Gy, producing a probability of DLT of 0.24. The 2-year FFLP is 59% (95% confidence interval [CI]: 32-79). Median and 2-year overall survival are 14.8 months (95% CI: 12.6-22.2) and 30% (95% CI 17-45). Twelve patients underwent resection (10 R0, 2 R1) and survived a median of 32 months. CONCLUSIONS High-dose radiation therapy with concurrent FDR-G can be delivered safely. The encouraging efficacy data suggest that outcome may be improved in unresectable patients through intensification of local therapy.

Pilot Clinical Trial of Hedgehog Pathway Inhibitor GDC-0449 (Vismodegib) in Combination with Gemcitabine in Patients with Metastatic Pancreatic Adenocarcinoma

Purpose: The hedgehog (HH) signaling pathway is a key regulator in tumorigenesis of pancreatic adenocarcinoma and is upregulated in pancreatic adenocarcinoma cancer stem cells (CSCs). GDC-0449 is an oral small-molecule inhibitor of the HH pathway. This study assessed the effect of GDC-0449–mediated HH inhibition in paired biopsies, followed by combined treatment with gemcitabine, in patients with metastatic pancreatic adenocarcinoma. Experimental Design: Twenty-five patients were enrolled of which 23 underwent core biopsies at baseline and following 3 weeks of GDC-0449. On day 29, 23 patients started weekly gemcitabine while continuing GDC-0449. We evaluated GLI1 and PTCH1 inhibition, change in CSCs, Ki-67, fibrosis, and assessed tumor response, survival and toxicity. Results: On pretreatment biopsy, 75% of patients had elevated sonic hedgehog (SHH) expression. On posttreatment biopsy, GLI1 and PTCH1 decreased in 95.6% and 82.6% of 23 patients, fibrosis decreased in 45.4% of 22, and Ki-67 in 52.9% of 17 evaluable patients. No significant changes were detected in CSCs pre- and postbiopsy. The median progression-free and overall survival for all treated patients were 2.8 and 5.3 months. The response and disease control rate was 21.7% and 65.2%. No significant correlation was noted between CSCs, fibrosis, SHH, Ki-67, GLI1, PTCH1 (baseline values or relative change on posttreatment biopsy), and survival. Grade ≥3 adverse events were noted in 56% of patients. Conclusion: We show that GDC-0449 for 3 weeks leads to downmodulation of GLI1 and PTCH1, without significant changes in CSCs compared with baseline. GDC-0449 and gemcitabine were not superior to gemcitabine alone in the treatment of metastatic pancreatic cancer. Clin Cancer Res; 20(23); 5937–45. ©2014 AACR.

Pomegranate Fruit Extract Impairs Invasion and Motility in Human Breast Cancer

Purpose. Pomegranate fruit extracts (PFEs) possess polyphenolic and other compounds with antiproliferative, pro-apoptotic and anti-inflammatory effects in prostate, lung, and other cancers. Because nuclear transcription factor-kB (NF-kB) is known to regulate cell survival, proliferation, tumorigenesis, and inflammation, it was postulated that PFEs may exert anticancer effects at least in part by modulating NF-kB activity. Experimental design. The authors investigated the effect of a novel, defined PFE consisting of both fermented juice and seed oil on the NF-kB pathway, which is constitutively active in aggressive breast cancer cell lines. The effects of the PFE on NF-kB—regulated cellular processes such as cell survival, proliferation, and invasion were also examined. Results. Analytical characterization of the bioactive components of the PFE revealed active constituents, mainly ellagitannins and phenolic acids in the aqueous PFE and conjugated octadecatrienoic acids in the lipid PFE derived from seeds.The aqueous PFE dose-dependently inhibited NF-kB—dependent reporter gene expression associated with proliferation, invasion, and motility in aggressive breast cancer phenotypes while decreasing RhoC and RhoA protein expression. Conclusion. Inhibition of motility and invasion by PFEs, coincident with suppressed RhoC and RhoA protein expression, suggests a role for these defined extracts in lowering the metastatic potential of aggressive breast cancer species.

Copper chelation in cancer therapy using tetrathiomolybdate: an evolving paradigm

Background: Tetrathiomolybdate (TM) is a novel anticancer and anti-angiogenic agent, which acts through copper chelation and NF-κB inhibition. Objective: This review summarizes the scientific rationale for the use of TM as an anticancer agent in human studies. Methods: A systematic review of the literature was conducted for the use of TM in cancer including preclinical, animal and human studies. The results of this search are summarized in this review. Results/conclusions: Copper chelation using TM has demonstrated efficacy in preclinical and animal models as an alternative and novel anti-angiogenic agent. Phase I and II clinical trials conducted in solid tumors using TM have demonstrated efficacy with favorable toxicity profile. The use of copper lowering as an anti-angiogenic strategy in the cancer chemopreventative setting remains to be investigated.

Prognostic significance of carbohydrate antigen 19-9 in unresectable locally advanced pancreatic cancer treated with dose-escalated intensity modulated radiation therapy and concurrent full-dose gemcitabine: analysis of a prospective phase 1/2 dose escalation study.

PURPOSE Although established in the postresection setting, the prognostic value of carbohydrate antigen 19-9 (CA19-9) in unresectable locally advanced pancreatic cancer (LAPC) is less clear. We examined the prognostic utility of CA19-9 in patients with unresectable LAPC treated on a prospective trial of intensity modulated radiation therapy (IMRT) dose escalation with concurrent gemcitabine. METHODS AND MATERIALS Forty-six patients with unresectable LAPC were treated at the University of Michigan on a phase 1/2 trial of IMRT dose escalation with concurrent gemcitabine. CA19-9 was obtained at baseline and during routine follow-up. Cox models were used to assess the effect of baseline factors on freedom from local progression (FFLP), distant progression (FFDP), progression-free survival (PFS), and overall survival (OS). Stepwise forward regression was used to build multivariate predictive models for each endpoint. RESULTS Thirty-eight patients were eligible for the present analysis. On univariate analysis, baseline CA19-9 and age predicted OS, CA19-9 at baseline and 3 months predicted PFS, gross tumor volume (GTV) and black race predicted FFLP, and CA19-9 at 3 months predicted FFDP. On stepwise multivariate regression modeling, baseline CA19-9, age, and female sex predicted OS; baseline CA19-9 and female sex predicted both PFS and FFDP; and GTV predicted FFLP. Patients with baseline CA19-9 ≤ 90 U/mL had improved OS (median 23.0 vs 11.1 months, HR 2.88, P<.01) and PFS (14.4 vs 7.0 months, HR 3.61, P=.001). CA19-9 progression over 90 U/mL was prognostic for both OS (HR 3.65, P=.001) and PFS (HR 3.04, P=.001), and it was a stronger predictor of death than either local progression (HR 1.46, P=.42) or distant progression (HR 3.31, P=.004). CONCLUSIONS In patients with unresectable LAPC undergoing definitive chemoradiation therapy, baseline CA19-9 was independently prognostic even after established prognostic factors were controlled for, whereas CA19-9 progression strongly predicted disease progression and death. Future trials should stratify by baseline CA19-9 and incorporate CA19-9 progression as a criterion for progressive disease.

Modulation of Angiogenesis for Cancer Prevention: Strategies Based On Antioxidants and Copper Deficiency

Although anti- angiogenesis strategies have generated much enthusiasm for therapeutic applications, it is still unknown whether they would be feasible for prevention. The possibility of interfering very early in tumor progression by modulating the cancer angiogenic switch is appealing. In this chapter, we review progress with in vitro and in vivo models that show that anti-angiogenic interventions may be amenable to long- term chemopreventive measures. In particular, some approaches that are nearly ready for major applications are anti-oxidant nutraceuticals and copper deficiency. We use these strategies as paradigms of how to make progress in this difficult but important area of translational research.

Three-Dimensional Echocardiography of Left Atrial Appendage Thrombus

Transesophageal echocardiography (TEE) is superior to transthoracic echocardiography (TTE) in evaluating the left atrial appendage (LAA) as a potential cardiac source of embolus in patients with stroke. We describe two such patients in whom a TEE and subsequently a three‐dimensional (3‐D) reconstruction of the LAA were performed. These case reports show that 3‐D echocardiography provides better visualization of LAA anatomy, and that a 3‐D description of LAA morphology may be the basis of describing normal and abnormal LAA.

Abstract A40: Cancer stem cells (CSC) and inhibition of hedgehog (Hh) pathway signaling in advanced pancreatic cancer: GDC-0449 in combination with gemcitabine (Gem).

Background: Pancreatic CSCs are a highly resistant subpopulation within a tumor that possess stem cell properties such as self-renewal and exhibit greater tumorigenicity and metastatic potential. These features are associated with reactivation of developmental pathways including the Hh signaling pathway. We previously reported that CD44+/CD24+/ ESA+ pancreatic CSCs express significantly elevated levels of Sonic Hh (Cancer Res, 2007). GDC-0449, a Smoothened antagonist, is an orally delivered small molecule inhibitor of the Hh pathway that has been evaluated in Phase 1 studies. We report here preliminary results of a clinical trial in patients with metastatic pancreatic cancer investigating sequential delivery of GDC-0449 and Gem providing a rationally designed, novel multi-targeted therapy. This trial importantly includes prospective evaluation of Hh pathway inhibition in pancreatic cancer by incorporating paired core biopsies of tumor before and after treatment with GDC-0449. Materials and Methods: Patients with previously untreated, metastatic pancreatic cancer were eligible. GDC-0449 was initiated as daily monotherapy for a 4-week cycle followed by the combination of daily GDC0449 with intravenous Gem days 1, 8 and 15 for each subsequent cycle. Two sets of 3 core biopsies were performed on each patient; one set prior to start of therapy and a second set 3 weeks after beginning GDC0449. A primary trial objective was to evaluate effects of GDC-0449 on pancreatic CSCs. Tumor biopsies were processed immediately after biopsy and allocated for correlative experiments. Fresh tissue was analyzed for CD44, CD24, and ESA expression by flow cytometry. Formalin-fixed tumor samples were evaluated for Ki67 by immunohistochemistry (IHC) and a proliferative index was calculated. Pretreatment Sonic Hh expression was also analyzed by IHC and assigned an H-Score based on review by a pancreatic pathologist. Clinical outcome parameters were measured, including progression free survival (PFS) at 3 months and response rate, and overall survival. Results: Twenty of a planned 25 patients have been accrued and undergone paired biopsies with 18 of 20 patients assessable for response after 3 cycles of therapy. Although a subset of patients had evidence of disease progression on GDC-0449 monotherapy per RECIST criteria, continuation of GDC0449 with addition of Gem resulted in significant response in several patients. RECIST-defined confirmed partial response was achieved in 5 patients (28%) with 4 additional patients having stable disease, yielding a 50% PFS rate at 3 months. Three patients have received treatment for ≥12 cycles. The percentage of pancreatic CSCs decreased in 56% of patients, and of these patients, the mean relative decrease was 60% ±22% (range, 16-87%). Proliferative index decreased in 54% of the patients (range, -11% to +28%). Sonic Hh expression was more highly expressed in patients that achieved a partial response or stable disease as compared to those with progression (mean H-score 285 vs 168, p = 0.016). Ongoing analysis of the effect of GDC-0449 on Hh pathway target genes is being conducted. Conclusion: Sequential delivery of GDC-0449 as monotherapy followed by combination with Gem is effective in providing clinical benefit to a subset of patients with metastatic pancreatic cancer. Of the biological correlates evaluated, pre-treatment Sonic Hh expression level is the best predictor of benefit with this regimen. Ongoing correlative studies are underway to further refine the best predictor of who will benefit from this combination therapy. Citation Format: Edward J. Kim, Gazala N. Khan, Kent Griffith, Joel Greenson, Naoko Takebe, Mark Zalupski, Diane Simeone. Cancer stem cells (CSC) and inhibition of hedgehog (Hh) pathway signaling in advanced pancreatic cancer: GDC-0449 in combination with gemcitabine (Gem). [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Progress and Challenges; Jun 18-21, 2012; Lake Tahoe, NV. Philadelphia (PA): AACR; Cancer Res 2012;72(12 Suppl):Abstract nr A40.

New Frontiers in Pancreatic Cancer Research

Pancreatic adenocarcinoma (PDA) is a highly lethal and aggressive malignancy with high mortality rates. It is critical to evaluate novel therapeutic strategies and targets for the treatment of this disease. In this article, the authors describe the important areas of focus in pancreatic cancer research, recent advances in these areas, and novel approaches that have the potential to bring about positive patient outcomes in this lethal disease. This article also focuses on recent developments in identifying new, more sensitive, and more specific blood biomarkers with potential use in the early detection of PDA.

Extremity Sarcoma: Positron Emission Tomography

Publisher Summary Sarcomas are rare, mesenchymal malignant tumors accounting for 1% of adult and 8% of pediatric cancers. Many of the sarcoma subtypes are characterized by histologic heterogeneity and may contain considerable morphological variation including cystic changes, hemorrhage, and necrosis. Imaging modalities frequently used in sarcoma management include roentgenography, computed tomography (CT), magnetic resonance imaging (MRI), bone scintigraphy, and positron emission tomography (PET). Standard radiography is very helpful in the diagnosis of primary bone lesions and can often distinguish benign from malignant processes. FDG-PET indirectly provides data regarding cellularity, mitotic rate, and carbohydrate metabolism. Thus, it can be of value in the work-up of connective tissue lesions. FDG-PET has been studied as an adjunct to conventional radiography in the diagnosis of malignancy, as a method to predict tumor grade, and as an aid to direct biopsy. FDG-PET has been studied as a tool to indirectly assess the histologic grade of sarcomas of bone and soft tissue; an adjunctive tool in the preoperative prognostic assessment of soft tissue sarcoma. FDG-PET is not superior to anatomic imaging methods in evaluating recurrent soft tissue sarcoma. FDG-PET is inferior to thoracic CT in detecting pulmonary metastases. FDG-PET has a role in directing needle biopsy of extremity soft tissue masses suspected of being sarcoma and in early detection of nonpulmonary visceral diseases.