Genetic target could help treat aggressive prostate cancer

Ann Arbor, MI-Results from in vitro and preclinical models provide proof of concept that SPINK1 (serine peptidase inhibitor, Kazal type 1) may be a viable therapeutic target for a subset of prostate cancer patients with an aggressive subtype of disease, say researchers from the University of Michigan, Ann Arbor.

Senior author Arul Chinnaiyan, MD, PhD, and colleagues had previously discovered in gene expression profiling studies, including samples from over 1,000 prostate cancer patients representing multiple independent cohorts, that SPINK1 was overexpressed in about 10% of prostate cancers. Additionally, they found SPINK1⁺ tumors were always negative for erythroblastosis virus E26 transformation-specific (ETS) gene fusions and had an aggressive phenotype, considering data on biochemical recurrence after prostatectomy and progression-free survival in endocrine-treated patients.

A correlation between SPINK1 overexpression and aggressive disease was subsequently corroborated by Finnish investigators, and because SPINK1 is an extracellular molecule that could be easily targeted with a monoclonal antibody, the University of Michigan team was particularly motivated to further investigate it as a potential therapeutic target. Initial studies proved that SPINK1 had oncogenic activity that could be blocked using a monoclonal antibody. Subsequently, testing in a mouse xenograft model showed that treatment with a monoclonal antibody to SPINK1 reduced cancer growth by 60% in animals with SPINK1⁺/ETS^– cancers but had no effect in SPINK1^– disease.

Testing to investigate the oncogenic activity of SPINK1 showed that a recombinant version of the protein stimulated proliferation and invasiveness of benign prostatic epithelial cells. After genetic knockdown of SPINK1 or exposure to a SPINK1 monoclonal antibody, SPINK1⁺/ETS^– prostate cancer cells exhibited decreased proliferation, invasiveness, and growth.

Role of EGFR investigated

A potential interaction between SPINK1 and epidermal growth factor receptor (EGFR) was also investigated recognizing structural similarity between SPINK1 and EGF, and showed that SPINK1 mediates part of its neoplastic activity through EGFR. This discovery led to testing of cetuximab (Erbitux), the commercially available EGFR monoclonal antibody, in the treatment of SPINK1⁺ prostate cancer in the xenograft mouse model. While less effective than the SPINK1 monoclonal antibody, cetuximab still acted in a SPINK1-specific way, Dr. Chinnaiyan reported.

In mice with SPINK1⁺/ETS^– prostate cancer xenografts, cetuximab alone attenuated tumor growth by more than 40% and by about 75% when it was combined with the SPINK1 monoclonal antibody. However, cetuximab had no effect in animals with SPINK1^–/ETS^– tumors.

"Previously, cetuximab was associated with disappointing results in a phase Ib/IIa trial of castrate-resistant metastatic prostate cancer where only three of 36 patients responded to the combination of cetuximab and doxorubicin [Adriamycin, Doxil]. However, that response rate is consistent with the 10% rate of SPINK1⁺ disease we have reported. We are hypothesizing that the patients who benefited from cetuximab might have been a SPINK1⁺ subset, and we believe a role of EGFR inhibition in prostate cancer, specifically in SPINK1⁺/ETS^– disease, requires further evaluation," Dr. Chinnaiyan said.

"No biomarker screening was performed in the cetuximab/doxorubicin clinical study. However, in order to test our theory, we are collaborating with that trial's investigators and will be testing biopsy tissue from enrolled patients for SPINK1 expression."

Dr. Chinnaiyan pointed out that the safety of SPINK1 inhibition could not be examined in the mouse model because the monoclonal antibody tested does not cross react with the form of SPINK that is endogenous to mice (SPINK3). However, because EGFR inhibitor therapy does not appear to have significant gastrointestinal or pancreatic toxicity, it is possible SPINK1 inhibition might have a similar safety profile.

"Testing is needed to identify possible safety issues, and if there is toxicity, if we can take advantage of some therapeutic window to achieve an acceptable risk:benefit ratio," Dr. Chinnaiyan said.