AACR: Androgen Deprivation Therapy Resistance in Prostate Cancer--A Hypothesis

Dean Tang, MD, PhD

Washington, DC-Targeting prostate cancer stem cells may be a method of treating prostate cancer while avoiding the development of resistance to androgen deprivation therapy (ADT), according to preclinical results presented at the annual meeting of the American Association for Cancer Research, held April 6–10 in Washington, DC.

Prostate cancer is one of the most commonly-diagnosed forms of cancer. In the advanced state, ADT is an effective treatment route that results in remission of the disease in most cases. Unfortunately, within 6 to 20 months, most patients who saw benefit from ADT relapse into resistant disease. In this presentation, Dean Tang, MD, PhD, from the University of Texas MD Anderson Cancer Center, showed data that may help to explain why ADT resistance occurs and how it can best be combated.

The expression of androgen receptor is thought to be a primary driver of prostate cancer, and prostate-specific antigen (PSA) is thought to be a clear-cut marker for disease. But Dr. Tang noted that this expression is highly heterogeneous, even within the same patient. “You will see a significant population of cells lacking expression of either [androgen receptor or prostate-specific antigen],” he remarked. In many patient samples, low expression of PSA indicated a high tumor grade, and in lab results Dr. Tang showed that the progenitor cells in prostate cancers had low PSA levels. As the cells differentiated and became more mature and epithelial, they gained PSA and became highly proliferative.

Dr. Tang next showed the results of a lineage tracing experiment in cultured prostate cancer cells where cells expressed green fluorescent protein driven by the levels of PSA. Cells that did not express PSA expressed red fluorescent protein instead. In a pair of movies, Dr. Tang demonstrated that sorted cells with expression of green fluorescent protein, which indicated high PSA levels, were only able to divide symmetrically into two clones. However, cells starting as red, which indicated low PSA expression, were able to undergo division that generated a differentiated, green fluorescent protein-expressing cell while maintaining the original parent. This suggested that the PSA-low cell population possessed an important characteristic of progenitor cells, the ability to asymmetrically divide and maintain their populations.

This dichotomy between PSA-positive and PSA-negative cells was confirmed in vivo using mouse xenografts in serial transplantation experiments. These entailed growing a tumor xenograft in mice and then using the tumor cells to transplant into a new mouse. The ability to form a new tumor is indicative of the level of self-renewal of the tumor and suggests a higher level of cancer progenitor cells. The results showed that, for several generations of passaging, the PSA-positive cells grew tumors more quickly, but as they were transplanted into new mice, their capacity diminished. In contrast, PSA-negative cells showed slow growth in the first few generations, but by the fourth passage, tumors were growing more quickly than PSA-positive cells. In addition, the PSA-negative cells maintained their tumorigenicity over more than 2 years’ worth of passages, suggesting these cells had the ability to self-renew indefinitely, another hallmark of progenitor cells.

The results of these studies present an interesting paradigm for prostate cancer management. Cells expressing high levels of PSA tend to express androgen receptor and are, therefore, more likely to be effectively killed by ADT, resulting in the clinical endpoint of pathologic complete response. This therapy, however, would leave the more slowly proliferating progenitor cells untouched, so they can be promoted to reconstitute a tumor, possibly at a distal site resulting in metastasis. Dr. Tang’s final thoughts on the matter summed up his hypothesis, “preferential targeting of these cells can be utilized in the adjuvant setting to prevent the recurrence of [prostate cancer] and, more importantly, metastasis.”