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Jose A, Kulkarni P, Thilakan J, Munisamy M, Malhotra AG, Singh J, Kumar A, Rangnekar VM, Arya N, Rao M. Integration of pan-omics technologies and three-dimensional in vitro tumor models: an approach toward drug discovery and precision medicine. Mol Cancer 2024; 23:50. [PMID: 38461268 PMCID: PMC10924370 DOI: 10.1186/s12943-023-01916-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2023] [Accepted: 12/15/2023] [Indexed: 03/11/2024] Open
Abstract
Despite advancements in treatment protocols, cancer is one of the leading cause of deaths worldwide. Therefore, there is a need to identify newer and personalized therapeutic targets along with screening technologies to combat cancer. With the advent of pan-omics technologies, such as genomics, transcriptomics, proteomics, metabolomics, and lipidomics, the scientific community has witnessed an improved molecular and metabolomic understanding of various diseases, including cancer. In addition, three-dimensional (3-D) disease models have been efficiently utilized for understanding disease pathophysiology and as screening tools in drug discovery. An integrated approach utilizing pan-omics technologies and 3-D in vitro tumor models has led to improved understanding of the intricate network encompassing various signalling pathways and molecular cross-talk in solid tumors. In the present review, we underscore the current trends in omics technologies and highlight their role in understanding genotypic-phenotypic co-relation in cancer with respect to 3-D in vitro tumor models. We further discuss the challenges associated with omics technologies and provide our outlook on the future applications of these technologies in drug discovery and precision medicine for improved management of cancer.
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Affiliation(s)
- Anmi Jose
- Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Pallavi Kulkarni
- Department of Biochemistry, All India Institute of Medical Sciences Bhopal, Bhopal, Madhya Pradesh, 462020, India
| | - Jaya Thilakan
- Department of Biochemistry, All India Institute of Medical Sciences Bhopal, Bhopal, Madhya Pradesh, 462020, India
| | - Murali Munisamy
- Department of Translational Medicine, All India Institute of Medical Sciences Bhopal, Bhopal, Madhya Pradesh, 462020, India
| | - Anvita Gupta Malhotra
- Department of Translational Medicine, All India Institute of Medical Sciences Bhopal, Bhopal, Madhya Pradesh, 462020, India
| | - Jitendra Singh
- Department of Translational Medicine, All India Institute of Medical Sciences Bhopal, Bhopal, Madhya Pradesh, 462020, India
| | - Ashok Kumar
- Department of Biochemistry, All India Institute of Medical Sciences Bhopal, Bhopal, Madhya Pradesh, 462020, India
| | - Vivek M Rangnekar
- Markey Cancer Center and Department of Radiation Medicine, University of Kentucky, Lexington, KY, 40536, USA
| | - Neha Arya
- Department of Translational Medicine, All India Institute of Medical Sciences Bhopal, Bhopal, Madhya Pradesh, 462020, India.
| | - Mahadev Rao
- Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India.
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Multiagent Chemotherapy Followed by Stereotactic Body Radiotherapy Versus Conventional Radiotherapy for Resected Pancreas Cancer. Am J Clin Oncol 2022; 45:450-457. [PMID: 36318696 DOI: 10.1097/coc.0000000000000947] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
BACKGROUND AND PURPOSE Chemotherapy followed by margin-negative resection (R0) is the treatment of choice for patients with localized pancreatic ductal adenocarcinoma (PDAC). Neoadjuvant multiagent chemotherapy (MAC) or MAC then radiotherapy (RT) may optimize surgical candidacy. The purpose of this study was to compare pathologic outcomes of MAC followed by conventionally fractionated radiotherapy (CRT) versus stereotactic body radiotherapy (SBRT) for patients with resected PDAC. METHODS Patients diagnosed with nonmetastatic PDAC between 2012 and 2017 and who received preoperative MAC or MAC+RT were identified in the National Cancer Database. Variables associated with R0 and overall survival were identified with logistic regression and Cox analysis (P<0.05). RESULTS A total of 5273 patients were identified (MAC: 3900, MAC+CRT: 955, MAC+SBRT: 418). The median RT dose/fraction (fx) in the MAC+CRT and MAC+SBRT cohorts was 50.4 Gy/28 fx and 33 Gy/5 fx. Patients receiving MAC+CRT versus MAC+SBRT had similar rates of ypT3-T4 disease (54% vs. 58%, P=0.187), R0 (87% vs. 84%, P=0.168), and pathologic complete response (pathologic complete response; 6% vs. 4%, P=0.052), however, MAC+CRT was associated with less regional lymphatic disease (ypN+: 28% vs. 41%, P<0.001). The median overall survival of patients receiving MAC+CRT versus MAC+SBRT was 24.6 versus 29.5 months (P=0.045). CONCLUSIONS For patients with resected PDAC, MAC+CRT, and MAC+SBRT had similar rates of R0 and pathologic complete response, although MAC+CRT was associated with lower ypN+. Prospective evaluation of neoadjuvant RT regimens with attention to radiation therapy design is warranted.
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Gupta N, Yelamanchi R. Pancreatic adenocarcinoma: A review of recent paradigms and advances in epidemiology, clinical diagnosis and management. World J Gastroenterol 2021; 27:3158-3181. [PMID: 34163104 PMCID: PMC8218366 DOI: 10.3748/wjg.v27.i23.3158] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 03/03/2021] [Accepted: 05/21/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is one of the dreaded malignancies for both the patient and the clinician. The five-year survival rate of pancreatic adenocarcinoma (PDA) is as low as 2% despite multimodality treatment even in the best hands. As per the Global Cancer Observatory of the International Agency for Research in Cancer estimates of pancreatic cancer, by 2040, a 61.7% increase is expected in the total number of cases globally. With the widespread availability of next-generation sequencing, the entire genome of the tumors is being sequenced regularly, providing insight into their pathogenesis. As invasive PDA arises from pancreatic intraepithelial neoplasia and mucinous neoplasm and intraductal papillary neoplasm, screening for them can be beneficial as the disease is curable with resection at an early stage. Routine preoperative biliary drainage has no role in patients suffering from PDA with obstructive jaundice. If performed, metallic stents are preferred over plastic ones. Minimally invasive procedures are preferred to open procedures as they have less morbidity. The duct-to-mucosa technique for pancreaticojejunostomy is presently widely practiced. The role of intraperitoneal drains after surgery for PDA is controversial. Neoadjuvant chemoradiotherapy has been proven to have a significant role both in locally advanced as well as in resectable PDA. Many new regimens and drugs have been added in the arsenal of chemoradiotherapy for metastatic disease. The roles of immunotherapy and gene therapy in PDA are being investigated. This review article is intended to improve the understanding of the readers with respect to the latest updates of PDA, which may help to trigger new research ideas and make better management decisions.
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Affiliation(s)
- Nikhil Gupta
- Department of Surgery, Atal Bihari Vajpayee Institute of Medical Sciences and Dr. Ram Manohar Lohia Hospital, Delhi 110001, India
| | - Raghav Yelamanchi
- Department of Surgery, Atal Bihari Vajpayee Institute of Medical Sciences and Dr. Ram Manohar Lohia Hospital, Delhi 110001, India
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Miccio JA, Talcott WJ, Patel T, Park HS, Cecchini M, Salem RR, Khan SA, Stein S, Kortmansky JS, Lacy J, Narang A, Herman J, Jabbour SK, Hallemeier CL, Johung K, Jethwa KR. Margin negative resection and pathologic downstaging with multiagent chemotherapy with or without radiotherapy in patients with localized pancreas cancer: A national cancer database analysis. Clin Transl Radiat Oncol 2020; 27:15-23. [PMID: 33392398 PMCID: PMC7772693 DOI: 10.1016/j.ctro.2020.12.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 12/11/2020] [Accepted: 12/12/2020] [Indexed: 01/02/2023] Open
Abstract
Purpose Margin-negative (R0) resection is the only potentially curative treatment for patients with pancreatic ductal adenocarcinoma (PDAC). Pre-operative multi-agent chemotherapy alone (MAC) or MAC followed by pre-operative radiotherapy (MAC + RT) may be used to improve resectability and potentially survival. However, the optimal pre-operative regimen is unknown. Methods Patients with non-metastatic PDAC from 2006 to 2016 who received pre-operative MAC or MAC + RT before oncologic resection were identified in the National Cancer Database. Univariable and multivariable (MVA) associates with R0 resection were identified with logistic regression, and survival was analyzed secondarily with the Kaplan Meier method and Cox regression analysis. Results 4,599 patients were identified (MAC: 3,109, MAC + RT: 1,490). Compared to those receiving MAC, patients receiving MAC + RT were more likely to have cT3-4 disease (76% vs 64%, p < 0.001) and cN + disease (33% vs 29%, p = 0.010), but were less likely to have ypT3-4 disease (59% vs 74%, p < 0.001) and ypN + disease (32% vs 55%, p < 0.001) and more likely to have a pathologic complete response (5% vs 2%, p < 0.001) and R0 resection (86% vs 80%, p < 0.001). On MVA, MAC + RT (OR 1.58, 95% CI 1.33-1.89, p < 0.001), evaluation at an academic center (OR 1.33, 95% CI 1.14-1.56, p < 0.001), and female sex (OR 1.43, 95% CI 1.23-1.67, p < 0.001) were associated with higher odds of R0 resection, while cT3-4 disease (OR 0.81, 95% CI 0.68-0.96, p = 0.013) was associated with lower odds of R0 resection. Conclusion For patients with localized PDAC who receive pre-operative MAC, the addition of pre-operative RT was associated with improved rates of R0 resection and pathologic response.
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Key Words
- AJCC, American Joint Committee on Cancer
- Chemotherapy
- IQR, interquartile range
- LR, logistic regression
- LVI, lymphovascular invasion
- MAC, multiagent chemotherapy
- MVA, multivariable analysis
- NCDB, National Cancer Database
- Neoadjuvant therapy
- OS, overall survival
- PDAC, pancreatic ductal adenocarcinoma
- Pancreatic cancer
- R0, margin negative
- RT, radiotherapy
- Radiotherapy
- Surgery
- UVA, univariable analysis
- pCR, pathologic complete response
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Affiliation(s)
- Joseph A Miccio
- Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520, USA
| | - Wesley J Talcott
- Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520, USA
| | - Timil Patel
- Department of Medical Oncology, Yale School of Medicine, New Haven, CT 06520, USA
| | - Henry S Park
- Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520, USA
| | - Michael Cecchini
- Department of Medical Oncology, Yale School of Medicine, New Haven, CT 06520, USA
| | - Ronald R Salem
- Department of Surgery, Yale School of Medicine, New Haven, CT 06520, USA
| | - Sajid A Khan
- Department of Surgery, Yale School of Medicine, New Haven, CT 06520, USA
| | - Stacey Stein
- Department of Medical Oncology, Yale School of Medicine, New Haven, CT 06520, USA
| | - Jeremy S Kortmansky
- Department of Medical Oncology, Yale School of Medicine, New Haven, CT 06520, USA
| | - Jill Lacy
- Department of Medical Oncology, Yale School of Medicine, New Haven, CT 06520, USA
| | - Amol Narang
- Department of Radiation Oncology & Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Joseph Herman
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA
| | - Salma K Jabbour
- Department of Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA
| | | | - Kimberly Johung
- Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520, USA
| | - Krishan R Jethwa
- Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520, USA
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Al Abbas AI, Hogg ME. ASO Author Reflections: Serum CA19-9 Utility in Pancreatic Adenocarcinoma in Patients Undergoing Neoadjuvant Therapy. Ann Surg Oncol 2020; 27:2015-2016. [PMID: 32172332 DOI: 10.1245/s10434-020-08342-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Indexed: 11/18/2022]
Affiliation(s)
- Amr I Al Abbas
- University of Pittsburgh, Pittsburgh, PA, USA.,University of Texas Southwestern, Dallas, TX, USA
| | - Melissa E Hogg
- University of Pittsburgh, Pittsburgh, PA, USA. .,Walgreens Building, Department of Surgery 2539, Northshore University Health System, Evanston, IL, USA.
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Oba A, Ho F, Bao QR, Al-Musawi MH, Schulick RD, Del Chiaro M. Neoadjuvant Treatment in Pancreatic Cancer. Front Oncol 2020; 10:245. [PMID: 32185128 PMCID: PMC7058791 DOI: 10.3389/fonc.2020.00245] [Citation(s) in RCA: 152] [Impact Index Per Article: 30.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Accepted: 02/13/2020] [Indexed: 12/13/2022] Open
Abstract
Thanks to the development of modern chemotherapeutic regimens, survival after surgery for pancreatic ductal adenocarcinoma (PDAC) has improved and pancreatologists worldwide agree that the treatment of PDAC demands a multidisciplinary approach. Neoadjuvant treatment (NAT) plays a major role in the treatment of PDAC since only about 20% of patients are considered resectable at the time of diagnosis. Moreover, increasing data demonstrating the benefits of NAT for borderline resectable/locally advanced PDAC are driving a shift from up-front surgery to NAT in the multidisciplinary treatment of even resectable PDAC. Our understanding of the role of NAT in PDAC has evolved from tumor shrinkage to controlling potential micrometastases and selecting patients who may benefit from radical resection. The present review gives an overview on the current literature of NAT concepts for BR/LA PDAC and resectable PDAC.
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Affiliation(s)
- Atsushi Oba
- Division of Surgical Oncology, Department of Surgery, University of Colorado, Anschutz Medical Campus, Denver, CO, United States.,Department of Hepatobiliary and Pancreatic Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Felix Ho
- Division of Surgical Oncology, Department of Surgery, University of Colorado, Anschutz Medical Campus, Denver, CO, United States
| | - Quoc Riccardo Bao
- Division of Surgical Oncology, Department of Surgery, University of Colorado, Anschutz Medical Campus, Denver, CO, United States.,Department of Surgery, Oncology, and Gastroenterology, University of Padua, Padua, Italy
| | - Mohammed H Al-Musawi
- Clinical Trials Office, Department of Surgery, University of Colorado, Anschutz Medical Campus, Denver, CO, United States
| | - Richard D Schulick
- Division of Surgical Oncology, Department of Surgery, University of Colorado, Anschutz Medical Campus, Denver, CO, United States
| | - Marco Del Chiaro
- Division of Surgical Oncology, Department of Surgery, University of Colorado, Anschutz Medical Campus, Denver, CO, United States
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