CTCs, PCa, and WNT

Circulating Tumor Cells, CTCs, are now capable of being extracted efficiently from patients. From Haber's Lab at Dana Farber his team has published a paper in Science describing the results. The results are worth examining.

They state in an earlier version on breast cancer:

Circulating tumor cells (CTCs) are present at low concentrations in the peripheral blood of patients with solid tumors. It has been proposed that the isolation, ex vivo culture, and characterization of CTCs may provide an opportunity to noninvasively monitor the changing patterns of drug susceptibility in individual patients as their tumors acquire new mutations. In a proof-of-concept study, we established CTC cultures from six patients with estrogen receptor–positive breast cancer. Three of five CTC lines tested were tumorigenic in mice. Genome sequencing of the CTC lines revealed preexisting mutations in the PIK3CA gene and newly acquired mutations in the estrogen receptor gene (ESR1), PIK3CA gene, and fibroblast growth factor receptor gene (FGFR2), among others. Drug sensitivity testing of CTC lines with multiple mutations revealed potential new therapeutic targets. With optimization of CTC culture conditions, this strategy may help identify the best therapies for individual cancer patients over the course of their disease. 

We have examined the pathways above extensively in the past and WNT is a well known target. I hear Haber talk this past week at NYAS and his talk was quite informative. I was especially impressed by the means used to extract CTCs, that alone is worth a look.

My general concern however is several fold:

1. CTCs can come from anywhere. As we have discussed before the work of Gundem et al demonstrated a complex proliferation of genetic profiles in AR PCa. Thus one may be able to gain some prognostic information but not localization.

2. There is always the issue of stem cells. Again what cells may get extravasated is not the same as what cells are proliferating.

3. Cell communication via exosomes is a concern as is the ECM issues of localized growth.

This is an extraordinary useful tool and definitely worth following. The current Science work on PCa states:

Prostate cancer is initially responsive to androgen deprivation, but the effectiveness of androgen receptor (AR) inhibitors in recurrent disease is variable. Biopsy of bone metastases is challenging; hence, sampling circulating tumor cells (CTCs) may reveal drug-resistance mechanisms. We established single-cell RNA-sequencing (RNA-Seq) profiles of 77 intact CTCs isolated from 13 patients (mean six CTCs per patient), by using microfluidic enrichment. Single CTCs from each individual display considerable heterogeneity, including expression of AR gene mutations and splicing variants. Retrospective analysis of CTCs from patients progressing under treatment with an AR inhibitor, compared with untreated cases, indicates activation of noncanonical Wnt signaling (P = 0.0064). Ectopic expression of Wnt5a in prostate cancer cells attenuates the antiproliferative effect of AR inhibition, whereas its suppression in drug-resistant cells restores partial sensitivity, a correlation also evident in an established mouse model. Thus, single-cell analysis of prostate CTCs reveals heterogeneity in signaling pathways that could contribute to treatment failure. 

 The last sentence is the most powerful and disturbingly consistent observation. PCa is just "too sneaky". It does not follow simple lines of development. It is not a BRAF V600 melanoma, it is not a Vogelstein colon cancer progression.

Frankly, it is for this reason alone that the USPTF recommendations on PSA testing are cruel and unusual. It is clear that PCa is a highly complex cancer and one that lends itself to multiple parallel paths resulting in some significantly high mortality rates. The very thought of taking the only tool and refusing to use it may, in my opinion, almost border on the criminal.