Matthew VanBrocklin

Assistant Professor of Surgery and
Adjunct Assistant Professor of Oncological Sciences

Hill Photo

B.S. Western Michigan University

M.S. Mayo Graduate School

Ph.D. Western Michigan University



Matthew VanBrocklin's Lab Page

Matthew VanBrocklin's PubMed Literature Search

Molecular Biology Program

Melanoma, Carcinoma, Non-Small-Cell Lung, Molecular Targets


Therapeutic agent development: We are interested in identifying novel molecular targets vital for tumor growth and progression and validating these candidates in pre-clinical models in order to develop rational pharmacological intervention strategies for melanoma and NSCLC patients. To this end, we utilize emerging technologies (RCAS/TVA, Bimolecular Fluorescence Complimentation, inducible CRISPR and high throughput screening) in order to investigate these factors and to identify small molecules that interfere with their function.  

The incidence of melanoma has been increasing at an alarming rate over the past twenty years. Approximately 76,100 new cases are expected in 2014 with nearly 9,710 resulting in death. It is the most rapidly increasing malignancy among young people in the United States and is the most common form of cancer in young adults 25-29 years old; over half of the patients are younger than 60 years old. Melanoma accounts for the majority of skin cancer deaths, and prognosis is poor for advanced stages of this disease. Patients with metastatic melanoma have limited treatment options and median survival ranges from 6-10 months. Current FDA-approved drugs for advanced melanoma include: Chemotherapy (dacarbazine), Immune modulators (interleukin-2 and ipilimumab), BRAF/MAPK directed agents (vemurafenib, dabrafenib and trametinib), but none offer much hope in the way of providing a lifelong cure for most patients.

Nearly 50% of all melanomas harbor an activating BRAF alteration (typically V600E) that constitutively activates the MAPK signaling pathway. Significant effort has been devoted to developing agents that inhibit BRAF/MEK in this cohort and initial clinical responses have been impressive. Unfortunately most patients develop resistance to these agents and relapse within months. Investigation into the mechanism(s) of resistance has revealed numerous ways to activate alternative survival signaling pathways and/or reactivate MAPK signaling despite continuous dosing. Given the diverse means of overcoming BRAF/MEK inhibition makes it difficult to develop dual targeting strategies. Therefore, additional molecular targets need to be identified which are germane to BRAF driven melanomas as well as NRAS and c-KIT associated melanomas.

To this end we have developed a novel high throughput melanoma mouse model capable of addressing tumor initiation, maintenance, progression and drug resistance based on the RCAS/TVA system. We are currently expanding this versatile model to incorporate a TET-inducible CRISPR (iCRISPR) component capable of deleting any endogenous gene specifically in the tumor at any given time post melanoma formation in vivo. This allows for the identification and validation of vital factors associated with melanoma survival with the ultimate goal of developing rational therapeutic approaches that provide durable responses in all subsets of melanomas.

Non-Small Cell Lung Carcinoma (NSCLC)
Lung cancer remains a significant health burden in the US and worldwide. It is responsible for more deaths than breast, colon, and prostate cancer combined. Lung cancer accounts for nearly 30% of all cancer deaths in the US and remains the leading cause of cancer deaths for both men and women. Presently, the five year overall survival rate for NSCLC remains at 15%, while small cell lung carcinoma survival rates are just six percent. It is clear that current therapies are inadequate and targeted agents may provide a more effective treatment option. RAS mutations (KRAS, HRAS or NRAS) are found in approximately one-third of all human malignancies and are highly prevalent in NSCLC. Notably, alterations in KRAS account for 90% of RAS mutations in lung adenocarcinomas. These mutations promote unregulated GTPase activity, leading to constitutive activation of RAS signaling. Alterations in KRAS promote resistance to receptor tyrosine kinase (RTK) directed inhibitors which target upstream components of RAS signaling. Therefore, KRAS or its downstream effectors are attractive candidates for molecular targeted therapeutic strategies. The primary downstream signaling effectors of RAS constitute the MAPK signaling pathway, the PI3K/AKT signaling cascade and the Ras-like Ral GTPases (RALA and RALB). Developing agents that specifically inhibit mutant RAS have proven elusive to date, therefore much attention has focused on targeting downstream MAPK and AKT signaling effectors. Despite the development and evaluation of numerous specific inhibitors of both signaling pathways none have demonstrated clinical efficacy in NSCLC.

We assessed RTK/KRAS signaling in a large panel of genetically diverse well characterized human NSCLC cell lines and identified that MAPK and/or PI3K signaling was not required for survival in the vast majority of these cells mirroring clinical observations. We did identify high level RALA and RALB signaling in all cell lines evaluated to date. RNAi directed at RALA and RALB induced significant cell death in most of the NSCLC cell lines evaluated regardless of EGFR/KRAS mutation status. Importantly, suppressing RALA/B or KRAS was effective in initiating apoptosis in most NSCLC cell lines. Developing pharmaceutical agents that directly inhibit small GTPases such as KRAS and RAL by traditional means has proven difficult. Therefore, we have developed an in-cell high throughput drug screening assay based on Bimolecular Fluorescence Complimentation (BiFC) in order to identify agents that can impair binding of active RAL or mutant KRAS to upstream activators and/or downstream effectors.


  1. Model of the TVA Receptor Determinants Required for Efficient Infection by Subgroup A Avian Sarcoma and Leukosis Viruses. Melder DC, Pike GM, VanBrocklin MW, Federspiel MJ J Virol. 2015 Feb 15;89(4):2136-48.
  2. Akt signaling accelerates tumor recurrence following ras inhibition in the context of ink4a/arf loss. Robinson GL, Robinson JP, Lastwika KJ, Holmen SL, Vanbrocklin MW. Genes Cancer. 2013 Nov;4(11-12):476-85.
  3. Ink4a/Arf loss promotes tumor recurrence following Ras inhibition. Vanbrocklin MW, Robinson JP, Lastwika KJ, McKinney AJ, Gach HM, Holmen SL. Neuro Oncol. 2012 Jan;14(1):34-42.
  4. Activated MEK cooperates with Ink4a/Arf loss or Akt activation to induce gliomas in vivo. Robinson JP, Vanbrocklin MW, Lastwika KJ, McKinney AJ, Brandner S, Holmen SL. Oncogene. 2011 Mar 17;30(11):1341-50.
  5. Akt signaling is required for glioblastoma maintenance in vivo. Robinson JP, Vanbrocklin MW, McKinney AJ, Gach HM, Holmen SL. Am J Cancer Res. 2011;1(2):155-167.
  6. Phase II trial to evaluate gemcitabine and etoposide for locally advanced or metastatic pancreatic cancer. Melnik MK, Webb CP, Richardson PJ, Luttenton CR, Campbell AD, Monroe TJ, O'Rourke TJ, Yost KJ, Szczepanek CM, Bassett MR, Truszkowski KJ, Stein P, Van Brocklin MW, Davis AT, Bedolla G, Vande Woude GF, Koo HM. Mol Cancer Ther. 2010 Aug;9(8):2423-9.
  7. Targeted delivery of NRASQ61R and Cre-recombinase to post-natal melanocytes induces melanoma in Ink4a/Arflox/lox mice. VanBrocklin MW, Robinson JP, Lastwika KJ, Khoury JD, Holmen SL. Pigment Cell Melanoma Res. 2010 Aug;23(4):531-41.
  8. Activated BRAF induces gliomas in mice when combined with Ink4a/Arf loss or Akt activation. Robinson JP, VanBrocklin MW, Guilbeault AR, Signorelli DL, Brandner S, Holmen SL. Oncogene. 2010 Jan 21;29(3):335-44.
  9. Met amplification and tumor progression in Cdkn2a-deficient melanocytes. Vanbrocklin MW, Robinson JP, Whitwam T, Guilbeault AR, Koeman J, Swiatek PJ, Vande Woude GF, Khoury JD, Holmen SL. Pigment Cell Melanoma Res. 2009 Aug;22(4):454-60.
  10. Mitogen-activated protein kinase inhibition induces translocation of Bmf to promote apoptosis in melanoma. VanBrocklin MW, Verhaegen M, Soengas MS, Holmen SL. Cancer Res. 2009 Mar 1;69(5):1985-94.
  11. Inhibition of avian leukosis virus replication by vector-based RNA interference. Chen M, Granger AJ, Vanbrocklin MW, Payne WS, Hunt H, Zhang H, Dodgson JB, Holmen SL. Virology. 2007 Sep 1;365(2):464-72.
  12. Differential oncogenic potential of activated RAS isoforms in melanocytes. Whitwam T, Vanbrocklin MW, Russo ME, Haak PT, Bilgili D, Resau JH, Koo HM, Holmen SL. Oncogene. 2007 Jul 5;26(31):4563-70.
  13. A novel BH3 mimetic reveals a mitogen-activated protein kinase-dependent mechanism of melanoma cell death controlled by p53 and reactive oxygen species. Verhaegen M, Bauer JA, Martín de la Vega C, Wang G, Wolter KG, Brenner JC, Nikolovska-Coleska Z, Bengtson A, Nair R, Elder JT, Van Brocklin M, Carey TE, Bradford CR, Wang S, Soengas MS. Cancer Res. 2006 Dec 1;66(23):11348-59.
  14. Antibody microarray profiling reveals individual and combined serum proteins associated with pancreatic cancer. Orchekowski R, Hamelinck D, Li L, Gliwa E, VanBrocklin M, Marrero JA, Vande Woude GF, Feng Z, Brand R, Haab BB. Cancer Res. 2005 Dec 1;65(23):11193-202.
  15. Simplified method for the construction of gene targeting vectors for conditional gene inactivation in mice. Wang PF, Kong D, Van Brocklin MW, Peng J, Zhang C, Potter SJ, Gao X, Teh BT, Zhang N, Williams BO, Holmen SL. Transgenics. 2005 4(3):215-8.
  16. Mitogen-activated protein kinase pathway-dependent tumor-specific survival signaling in melanoma cells through inactivation of the proapoptotic protein bad. Eisenmann KM, VanBrocklin MW, Staffend NA, Kitchen SM, Koo HM. Cancer Res. 2003 Dec 1;63(23):8330-7.
  17. Apoptosis and melanogenesis in human melanoma cells induced by anthrax lethal factor inactivation of mitogen-activated protein kinase kinase. Koo HM, VanBrocklin M, McWilliams MJ, Leppla SH, Duesbery NS, Vande Woude GF. Proc Natl Acad Sci USA. 2002 Mar 5;99(5):3052-7.
  18. Capsid-targeted viral inactivation can eliminate the production of infectious murine leukemia virus in vitro. VanBrocklin M, Federspiel MJ. Virology. 2000 Feb 1;267(1):111-23.
  19. Extended analysis of the in vitro tropism of porcine endogenous retrovirus. Wilson CA, Wong S, VanBrocklin M, Federspiel MJ. J Virol. 2000 Jan;74(1):49-56.
  20. The EV-O-derived cell line DF-1 supports the efficient replication of avian leukosis-sarcoma viruses and vectors. Schaefer-Klein J, Givol I, Barsov EV, Whitcomb JM, VanBrocklin M, Foster DN, Federspiel MJ, Hughes SH. Virology. 1998 Sep 1;248(2):305-11.
  21. Expression of a murine leukemia virus Gag-Escherichia coli RNase HI fusion polyprotein significantly inhibits virus spread. VanBrocklin M, Ferris AL, Hughes SH, Federspiel MJ. J Virol. 1997 Apr;71(4):3312-8.
  22. Efficient lipid-mediated transfection of DNA into primary rat hepatocytes. Holmen SL, Vanbrocklin MW, Eversole RR, Stapleton SR, Ginsberg LC. In Vitro Cell Dev Biol Anim. 1995 May;31(5):347-51.

to page top

Last Updated: 5/24/18