Details of the Drug Combination

General Information of Drug Combination (ID: DCEL30Y)

• Drug Combination Name: Bevacizumab + Trastuzumab
• Indication: Breast cancer; Status: Phase 1 [1]
• Component Drugs:
  Bevacizumab (DMSD1UN): Monoclonal antibody
  Trastuzumab (DMZQOUX): Antibody

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Bevacizumab

Disease Entry	ICD 11	Status	REF
Adenocarcinoma	2D40	Approved	[2]
Adult acute monocytic leukemia	N.A.	Approved	[3]
Biliary tract cancer	2C17	Approved	[4]
Childhood acute megakaryoblastic leukemia	N.A.	Approved	[3]
Cholangiocarcinoma	2C12.10	Approved	[5]
Colon adenocarcinoma	N.A.	Approved	[6]
Colorectal carcinoma	N.A.	Approved	[7]
Esophageal disorder	N.A.	Approved	[8]
Glioblastoma	2A00	Approved	[9]
Glioblastoma of brain	2A00.00	Approved	[10]
Hemangioblastoma	N.A.	Approved	[11]
Intracranial meningioma	N.A.	Approved	[12]
Lung adenocarcinoma	N.A.	Approved	[13]
Malignant epithelial tumor of ovary	N.A.	Approved	[14]
Metastatic colorectal cancer	2B91	Approved	[15]
Non-small-cell lung cancer	2C25.Y	Approved	[16]
Rectal adenocarcinoma	2B92	Approved	[17]
Von hippel-lindau disease	5A75	Approved	[18]
Colorectal cancer	2B91.Z	Phase 3	[19]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 2/3	[20]
Brain metastases	2D50	Phase 2	[19]
Lung cancer	2C25.0	Phase 1	[19]
Solid tumour/cancer	2A00-2F9Z	Phase 1	[21]
Ovarian cancer	2C73	Application submitted	[21]
Adult glioblastoma	N.A.	Investigative	[22]
Colon cancer	2B90.Z	Investigative	[23]
Fallopian tube cancer	2C74	Investigative	[24]
Hereditary hemorrhagic telangiectasia	LA90.00	Investigative	[25]
Lung large cell carcinoma	N.A.	Investigative	[26]

Bevacizumab Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Vascular endothelial growth factor A (VEGFA)	TTOHSBA	VEGFA_HUMAN	Inhibitor	[31]
HUMAN vascular endothelial growth factor (VEGF)	TT140V6	VEGFA_HUMAN; VEGFB_HUMAN; VEGFC_HUMAN; VEGFD_HUMAN	Inhibitor	[20]

Bevacizumab Interacts with 6 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Mastermind-like protein 2 (MAML2)	OT1TSVAR	MAML2_HUMAN	Increases ADR	[32]
6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3)	OT25JBA3	F263_HUMAN	Increases ADR	[32]
TGF-beta receptor type-2 (TGFBR2)	OT3P7GZP	TGFR2_HUMAN	Increases ADR	[32]
Beta-parvin (PARVB)	OT9OGVWX	PARVB_HUMAN	Increases ADR	[32]
Mitochondrial peptide methionine sulfoxide reductase (MSRA)	OTBS15SD	MSRA_HUMAN	Increases ADR	[32]
Synaptic vesicle glycoprotein 2C (SV2C)	OTIH108W	SV2C_HUMAN	Increases ADR	[32]

Indication(s) of Trastuzumab

Disease Entry	ICD 11	Status	REF
Breast cancer	2C60-2C65	Approved	[27]
Inflammatory breast cancer	2C62	Approved	[28]
Lung cancer	2C25.0	Approved	[29]
Gastric adenocarcinoma	2B72	Application submitted	[21]
HER2-positive breast cancer	2C60-2C65	Application submitted	[21]
Gastric cancer	2B72	Investigative	[30]

Trastuzumab Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Erbb2 tyrosine kinase receptor (HER2)	TT6EO5L	ERBB2_HUMAN	.	[33]

Trastuzumab Interacts with 1 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Receptor tyrosine-protein kinase erbB-2 (ERBB2)	OTOAUNCK	ERBB2_HUMAN	Increases ADR	[34]

References

• [1] ClinicalTrials.gov (NCT00365365) Safety & Efficacy of Three Docetaxel-Based Chemotherapy Regimens Plus Bevacizumab With or Without Trastuzumab for Adjuvant Treatment of Patients With Breast Cancer
• [2] Bevacizumab in metastatic small-bowel adenocarcinoma: A systematic review and meta-analysis. Rare Tumors. 2019 May 14;11:2036361318825413.
• [3] A standard database for drug repositioning. Sci Data. 2017 Mar 14;4:170029.
• [4] Angiogenesis in biliary tract cancer: targeting and therapeutic potential. Expert Opin Investig Drugs. 2021 Apr;30(4):411-418.
• [5] Hepatobiliary Cancers, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2021 May 1;19(5):541-565.
• [6] Long-term response to sintilimab, bevacizumab and chemotherapy in heavily pretreated microsatellite stable colon cancer. Immunotherapy. 2023 Feb;15(3):127-133.
• [7] Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol. 2015 May;16(5):499-508.
• [8] Advances in targeted therapy for esophageal cancer. Signal Transduct Target Ther. 2020 Oct 7;5(1):229.
• [9] Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol. 2009 Oct 1;27(28):4733-40.
• [10] Synchronous glioblastoma and brain metastases: illustrative case. J Neurosurg Case Lessons. 2022 Mar 21;3(12):CASE21714.
• [11] Intra-arterial Bevacizumab for Posterior Fossa Hemangioblastoma. Cureus. 2022 Dec 17;14(12):e32624.
• [12] The controversial role of Bevacizumab in the treatment of patients with intracranial meningioma: a comprehensive literature review. Expert Rev Anticancer Ther. 2020 Mar;20(3):197-203.
• [13] International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol. 2011 Feb;6(2):244-85.
• [14] Gynecologic cancer in pregnancy. Gynecol Oncol. 2020 Jun;157(3):799-809.
• [15] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [16] Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006 Dec 14;355(24):2542-50.
• [17] Phase II randomized trial of capecitabine with bevacizumab and external beam radiation therapy as?preoperative treatment for patients with resectable locally advanced rectal adenocarcinoma: long term?results. BMC Cancer. 2020 Nov 27;20(1):1164.
• [18] 89Zr-Bevacizumab PET Visualizes Disease Manifestations in Patients with von Hippel-Lindau Disease. J Nucl Med. 2016 Aug;57(8):1244-50.
• [19] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [20] ClinicalTrials.gov (NCT04275414) Bevacizumab in Severe or Critical Patients With COVID-19 Pneumonia (BEST-CP)
• [21] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [22] Lomustine and Bevacizumab in Progressive Glioblastoma. N Engl J Med. 2017 Nov 16;377(20):1954-1963.
• [23] Colon cancer. Crit Rev Oncol Hematol. 2010 May;74(2):106-33.
• [24] OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol. 2012 Jun 10;30(17):2039-45.
• [25] Hereditary hemorrhagic telangiectasia: diagnosis and management from the hematologist's perspective. Haematologica. 2018 Sep;103(9):1433-1443.
• [26] Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc. 2008 May;83(5):584-94.
• [27] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 5082).
• [28] Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012 Jan;13(1):25-32.
• [29] Trastuzumab Deruxtecan in HER2-Mutant Non-Small-Cell Lung Cancer. N Engl J Med. 2022 Jan 20;386(3):241-251.
• [30] The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer. Nature. 2021 Dec;600(7890):727-730.
• [31] FDA Approved Drug Products from FDA Official Website. 2004. Application Number: (ANDA) 125085.
• [32] Genetic variant predicts bevacizumab-induced hypertension in ECOG-5103 and ECOG-2100. Br J Cancer. 2014 Sep 9;111(6):1241-8. doi: 10.1038/bjc.2014.430. Epub 2014 Aug 12.
• [33] Her2/neu is not a commonly expressed therapeutic target in melanoma -- a large cohort tissue microarray study. Melanoma Res. 2004 Jun;14(3):207-10.
• [34] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.