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Pancreatic Neoplasms: HELP
Articles by Khaldoun Almhanna
Based on 7 articles published since 2010
(Why 7 articles?)

Between 2010 and 2020, K. Almhanna wrote the following 7 articles about Pancreatic Neoplasms.
+ Citations + Abstracts
1 Review Defining new paradigms for the treatment of pancreatic cancer. 2011

Almhanna, Khaldoun / Philip, Philip A. ·Department of Gastrointestinal Oncolgy, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. ·Curr Treat Options Oncol · Pubmed #21461670.

ABSTRACT: Pancreatic cancer (PC) is the fourth leading cause of cancer death in the United States. Despite significant improvement in understanding disease biology, the 5-year survival rates remain less than 5%. Targeted agents failed to add any meaningful survival benefit in this patient population despite very promising pre-clinical data. The new paradigm for the treatment of PC must emphasize validation of targeted agents in the appropriate pre-clinical models, identification of predictive markers for disease response, and extending range of targets into cancer stem cells and tumor microenvironment. It is also necessary to perform studies that are designed to address the various stages of disease with respect to study endpoints and application of a multimodality approach in management. Phase III trials should only be considered when a strong efficacy signal is demonstrated in phase II studies that is based on a survival endpoint. This review will focus on the development of novel treatments in pancreas cancer and the proposed design of future clinical trials.

2 Review MDM2 inhibitors for pancreatic cancer therapy. 2010

Azmi, Asfar S / Philip, Philip A / Almhanna, Khaldoun / Beck, Frances W / Sarkar, Fazlul H / Mohammad, Ramzi M. ·Hematology and Oncology, Internal Medicine, Wayne State University School of Medicine, Karmanos Cancer Institute, 732 HWCRC, 4100 John R Street, Detroit, MI 48201, USA. ·Mini Rev Med Chem · Pubmed #20377522.

ABSTRACT: MDM2 protein negatively regulates p53 and is found to be elevated in cancer cells. An attractive approach towards targeting MDM2 is the use of small molecule inhibitors that bind to MDM2 and disrupt the MDM2-p53 interaction. Our laboratory has been at the forefront in testing MDM2 inhibitors in pancreatic adenocarcinoma (PaCa), a deadly disease with approximately 50% wild-type p53 population. Emerging evidence suggests that apart from regulating p53, MDM2 can influence other key molecules involved in cancer. This review summarizes recent advancements in the development of MDM2 inhibitors, their novel primary and secondary targets and highlights their potential as therapeutics for PaCa.

3 Clinical Trial A phase II study of antibody-drug conjugate, TAK-264 (MLN0264) in previously treated patients with advanced or metastatic pancreatic adenocarcinoma expressing guanylyl cyclase C. 2017

Almhanna, Khaldoun / Wright, David / Mercade, Teresa Macarulla / Van Laethem, Jean-Luc / Gracian, Antonio Cubillo / Guillen-Ponce, Carmen / Faris, Jason / Lopez, Carolina Muriel / Hubner, Richard A / Bendell, Johanna / Bols, Alain / Feliu, Jaime / Starling, Naureen / Enzinger, Peter / Mahalingham, Devalingham / Messersmith, Wells / Yang, Huyuan / Fasanmade, Adedigbo / Danaee, Hadi / Kalebic, Thea. ·Department of Gastrointestinal Oncology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL, 33612, USA. Khaldoun.Almhanna@moffitt.org. · Florida Cancer Specialists, Tampa, FL, USA. · Vall d'Hebron University Hospital, Barcelona, Spain. · Erasme University Hospital, Brussels, Belgium. · HM Universitario Sanchinarro, Centro Integral Oncológico Clara Campal (CIOCC), Madrid, Spain. · Departamento de Ciencias Médicas Clínicas, Universidad San Pablo CEU, Madrid, Spain. · Ramón y Cajal University Hospital, Madrid, Spain. · Massachusetts General Hospital Cancer Center, Boston, MA, USA. · Hospital Universitario Virgen de la Victoria, Málaga, Spain. · The Christie NHS Foundation Trust, Manchester, UK. · Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN, USA. · Brugge Oostende Oncologisch Centrum, Bruges, Belgium. · CIBERONC, La Paz University Hospital, Madrid, Spain. · The Royal Marsden NHS Foundation Trust, London, UK. · Dana Farber Cancer Institute, Boston, MA, USA. · University of Texas Health Science Center, San Antonio, TX, USA. · University of Colorado, Aurora, CO, USA. · Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA. ·Invest New Drugs · Pubmed #28527133.

ABSTRACT: Background This phase II open-label, multicenter study evaluated the efficacy, safety, and tolerability of TAK-264 in previously treated patients with advanced or metastatic pancreatic adenocarcinoma expressing guanylyl cyclase C (GCC). Methods Patients with advanced or metastatic pancreatic adenocarcinoma expressing GCC (H-score ≥ 10) received TAK-264 1.8 mg/kg on day 1 of a 21-day cycle as a 30-min intravenous infusion for up to 1 year or until disease progression or unacceptable toxicity. The primary objective was overall response rate (ORR [complete response + partial response (PR)]). Secondary objectives included evaluations of the safety and pharmacokinetic profile of TAK-264 (NCT02202785). Results 43 patients were enrolled and treated with 1.8 mg/kg TAK-264: 11, 15, and 17 patients with low, intermediate, and high GCC expression, respectively. Median number of treatment cycles received was two (range 1-10). The ORR was 3%, including one patient with intermediate GCC expression who achieved a PR. All patients experienced ≥1 adverse events (AE). The majority of patients experienced grade 1/2 AEs affecting the gastrointestinal tract. Fifteen (35%) patients experienced ≥grade 3 drug-related AEs; five (12%) patients had a serious AE. The most common (≥10% of patients) all-grade drug-related AEs were nausea (33%), fatigue (28%), neutropenia (23%), decreased appetite (23%), vomiting (16%), asthenia (16%), and alopecia (14%). Conclusions TAK-264 demonstrated a manageable safety profile; however, the low efficacy of TAK-264 observed in this study did not support further clinical investigation.

4 Article Differentially expressed miRNAs in the plasma may provide a molecular signature for aggressive pancreatic cancer. 2010

Ali, Shadan / Almhanna, Khaldoun / Chen, Wei / Philip, Philip A / Sarkar, Fazlul H. · ·Am J Transl Res · Pubmed #21139804.

ABSTRACT: Pancreatic cancer (PC) has the poorest overall survival rate among all human cancers because of late diagnosis and absence of screening tools. We compared the expression profile of microRNAs (miRNAs) in the plasma of patients diagnosed with PC (n=50) with healthy volunteers (n=10). Data was further validated by quantitative realtime PCR and cell-based assays. Thirty-seven miRNAs were down-regulated and 54 were up-regulated in plasma from patients with PC. The expression of miR-21 was significantly higher, and the expression of let-7 family (especially let-7d) and miR-146a was significantly lower in PC. Most interestingly, the expression of miR-21 was correlated with worse survival, and the expression of let-7 was inversely correlated with survival in this pilot study with mixed patient population. Moreover, we found that miR-21 family was markedly over-expressed in chemo-resistant PC cell lines, which was consistent with the plasma data from PC patients. Our previous studies have shown increased expression of miR-21 with concomitant loss of PTEN expression in PC cells, which is consistent with our current findings showing the loss of three additional targets of miR-21 (PDCD4, Maspin and TPM1). These results suggest that identifying and validating the expression of miRNAs in newly diagnosed patients could serve as potential biomarker for tumor aggressiveness, and such miRNAs could be useful for the screening of high-risk patients, and may also serve as targets for future drug development.

5 Article Impact of race, age, and socioeconomic status on participation in pancreatic cancer clinical trials. 2010

El-Rayes, Bassel F / Jasti, Pallavi / Severson, Richard K / Almhanna, Khaldoun / Philip, Philip A / Shields, Anthony / Zalupski, Mark / Heilbrun, Lance K. ·Division of Hematology/Oncology, Barbara Ann Karmanos Cancer Institute and Wayne State University, Detroit, MI, USA. ·Pancreas · Pubmed #20467351.

ABSTRACT: OBJECTIVES: Over 18 years, 7 phase 2 trials in advanced pancreatic cancer (APC) were conducted at Karmanos Cancer Institute (KCI). We sought factors that influenced the selection of patients for clinical trials and explored differences in overall survival (OS) of patients treated on clinical trials versus standard of care. METHODS: The target population was patients with APC diagnosed between January 1, 1986, and December 31, 2003. Patients were divided into 3 mutually exclusive groups: treated on clinical trials at KCI (t-KCI), treated at KCI but not on a clinical trial (KCI), or treated at non-KCI institutions (n-KCI). RESULTS: Eight thousand two hundred thirty patients met study criteria: 6470 n-KCI, 1642 KCI, and 118 t-KCI. Significant differences were observed across the 3 groups with respect to age, race, stage, grade, and socioeconomic status. Median OS was higher in t-KCI (8.5 months) than in KCI (5.0 months) or n-KCI (2.8 months) and could not be accounted for by variations in baseline characteristics. CONCLUSIONS: Patients enrolled on clinical trials were younger, had better socioeconomic status, and were less often African American. Patients with APC treated at academic institutions may have longer OS than patients treated in the community. Clinical trials seem to offer a survival advantage for patients with APC.

6 Article A single institution review of adjuvant therapy outcomes for resectable pancreatic adenocarcinoma: outcome and prognostic indicators. 2010

Kim, Richard / Tsao, Raymond / Tan, Ann / Byrne, Mike / Almhanna, Khaldoun / Lazaryan, Aleksander / Elson, Paul / Pelley, Robert J. ·Taussig Cancer Center, Cleveland Clinic, R35 9500 Euclid Ave, Cleveland, OH 44195, USA. KimR3@ccf.org ·J Gastrointest Surg · Pubmed #20446118.

ABSTRACT: INTRODUCTION: A large single-institution series of patients who recently underwent pancreaticoduodenectomy for resectable pancreatic cancer was analyzed to determine prognostic factors for overall survival, including the impact of adjuvant radiation and chemotherapy. METHODS: Medical records were reviewed for 179 consecutive patients treated at The Cleveland Clinic with pancreaticoduodenectomy for resectable pancreatic adenocarcinoma from 1999 to 2006. Clinical data were collected, and Kaplan-Meier method was used to estimate overall survival. Univariate and multivariate analysis was performed. RESULTS: One hundred seventy-nine patients with pT1-3N0-1M0 pancreatic cancer met the above criteria. But analysis was available for 158 patients. Median age at diagnosis was 67 (range 35-93). Peri-operative mortality rate was 0.6%. On univariate analysis, poor prognostic factors for overall survival were poorly differentiated histology, lymph node positive disease, elevated alkaline phosphatase, elevated total bilirubin, elevated AST, age at diagnosis >70, and high T stage. On multivariate analysis, poorly differentiated histology (p = .001), age >70 (p = .007), lymph node involvement (> or = 3 positive vs <3, p = .03), and elevated LFTs (alkaline phosphatase and/or bilirubin and/or AST; p = .002) were independent predictors of survival. Median survival for patients treated with adjuvant chemo-XRT was 28.4 months (vs. 11.8 months for patients receiving no adjuvant therapy (p < .001) in both univariate analysis and in multivariate analysis after adjusting for the independent prognostic factors described above). Median survival for patients treated with adjuvant chemotherapy alone had not yet been reached (p < .001 compared to no adjuvant therapy, in both univariate and multivariate analysis). CONCLUSION: In the twenty-first century, curative-intent surgery for pancreatic cancer at large academic institutions can have very low mortality rates. Pathology findings are valuable prognostic markers in resected pancreatic cancer. Few studies have examined the prognostic value of preoperative LFTs or lymph node ratio, and our analysis indicates they may have prognostic value-this should be confirmed in other series. Pts who receive adjuvant therapy (chemo-XRT or chemotherapy) appear to live longer than patients who receive no adjuvant therapy in this retrospective analysis.

7 Article Reactivation of p53 by novel MDM2 inhibitors: implications for pancreatic cancer therapy. 2010

Azmi, Asfar S / Philip, Philip A / Aboukameel, A / Wang, Zhiwei / Banerjee, Sanjeev / Zafar, Syed F / Goustin, Anton-Scott / Almhanna, K / Yang, Dajun / Sarkar, Fazlul H / Mohammad, Ramzi M. ·Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA. ·Curr Cancer Drug Targets · Pubmed #20370686.

ABSTRACT: The present study is the first to show in pancreatic cancer (PC) the growth inhibition and apoptosis by novel MDM2 inhibitors (MI-319 & 219) through reactivation of p53 pathway. Our results highlight two new secondary targets of MDM2 inhibitor 'SIRT1' and Ku70. SIRT1 which has a role in ageing and cancer and is known to regulate p53 signaling through acetylation. Ku70 is a key component of non-homologous end joining machinery in the DNA damage pathway and is known to regulate apoptosis by blocking Bax entry into mitochondria. Growth inhibition and apoptosis by MI-219, MI-319 was accompanied by increase in levels of p53 along with p21(WAF1) and the proapoptotic Puma. SiRNA against p21(WAF1) abrogated the growth inhibition of PC cells confirming p21(WAF1) as a key player downstream of activated p53. Immunoprecipitation-western blot analysis revealed reduced association of MDM2-p53 interaction in drug exposed PC cells. In combination studies, the inhibitors synergistically augmented anti-tumor effects of therapeutic drug gemcitabine both in terms of cell growth inhibition as well as apoptosis. Surface plasmon resonance studies confirmed strong binding between MI-319 and Ku70 (K(D) 170 nM). Western blot revealed suppression of SIRT1 and Ku70 with simultaneous upregulation of acetyl-p53 (Lys379) and Bax. Co-Immunoprecipitation studies confirmed that MI-319 could disrupt Ku70-Bax and SIRT1-Bax interaction. Further, using wt-p53 xenograft of Capan-2, we found that oral administration of MI-319 at 300 mg/kg for 14 days resulted in significant tumor growth inhibition without any observed toxicity to the animals. No tumor inhibition was found in mut-p53 BxPC-3 xenografts. In light of our results, the inhibitors of MDM2 warrant clinical investigation as new agents for PC treatment.