The seminal study by Wang and colleagues reported in the Journal of the National Cancer Institute1 and reviewed in this issue of The ASCO Post suggests a potential new therapeutic option in the treatment of advanced prostate cancer. The authors draw attention to the reliance of cancer cells on amino acids and the subsequent nutrient transporters that supply tumors with this metabolic fuel. The amino acid transporters, broken into various families, mediate the transport of amino acids, which then influence cellular signaling pathways.
The current report shows the dependence of prostate cancer cells on amino acid uptake through the L-type amino acid transporter (LAT) family of transporters in order to proliferate through activation of the mammalian target of rapamycin complex 1 (mTORC1). The importance of the LAT transporters has been evaluated in preclinical experiments in multiple cancer cell lines,2 and this study expands upon previous work by Holst and colleagues3 illustrating the importance of LAT1 and LAT3 in prostate cancer growth and oncogenesis to now demonstrate the interplay between androgen receptor–dependent genes and the LAT transporters, the role of the transporters in castrate-resistant disease, and the effect of inhibition of transport on tumor growth and metastasis.
The authors suggest that targeting LAT transporters, and thus influencing the uptake of leucine, affects tumor growth and metastasis through inhibition of the mTORC1 signaling pathway and M-phase cell-cycle signals. Consequently, these transporters are potential therapeutic targets in the treatment of advanced prostate cancer, including castrate-resistant disease.
Clinical Impact: Therapeutic Target
Treatment options for metastatic prostate cancer have expanded markedly in the last few years. However, many of these newer therapies effectively decrease circulating testosterone or strengthen androgen receptor blockade. As we improve the manipulation of the androgen axis, we have found that the response to subsequent therapies diminishes.4 This suggests that prostate cancer cells, much like any cancer cell, adapt to rely on varied growth mechanisms and continued mutagenesis for survival.
Targeting the LAT transporters is a potential new mechanism to control advanced prostate cancer. Importantly, this approach is different from the elegant modulation of the androgen receptor that we now rely on in the treatment of castrate-resistant disease.
Analysis of microarray data in the study showed that many of the transporters are regulated by the androgen receptor signaling pathway as well as the activating transcription factor 4 (ATF4)-mediated amino acid pathway. Androgen deprivation has been shown to alter the expression levels of transporter genes, and ATF4 expression is increased in metastasis.
The data presented in the study suggest that there is interplay between amino acid transport and castrate-resistant disease. Genes associated with the mTORC1 pathway and M-phase cell-cycle genes were altered in castrate-resistant tumor samples; and treatment with BCH, a LAT inhibitor, revealed that genes that are upregulated in castrate-resistant disease were effectively downregulated by treatment in cell culture.
In vivo experiments also supported the necessity of amino acids in prostate cancer development and metastasis, since knockdown of the LAT1 or LAT3 transporter reduced tumor formation, decreased the size of tumors, and decreased the number of noted metastases. Through in vivo knockdown of the transporter gene, or in vitro inhibition by BCH, the growth of prostate cancer was diminished, supporting the potential for success with pharmacologic inhibition in a clinical setting.
Clinical Impact: Biomarker
Compared to a number of other malignant neoplasms, there is a paucity of biomarker data in advanced prostate cancer. To address this, the field is rightly focused on exploration and validation of biomarkers to help guide therapeutic decision-making. In addition to potential as a therapeutic target, the LAT family of transporters may also serve as a biomarker. LAT1 expression has been postulated as a biomarker in lung cancer5 and may serve as one in prostate cancer, as suggested by the altered expression of LAT1 in association with Gleason score.
The gene expression of ATF4 was also upregulated by leucine deprivation and was found to be upregulated in the gene profiles of metastatic castrate-resistant samples, and this may indicate advanced malignancy. LAT inhibition repressed cell-cycle genes, yet these genes were found to be enriched in metastatic samples compared to primary prostate cancer tissue, and some of these genes were associated with poor survival. Additionally, neoadjuvant therapy altered LAT3 expression. Thus, LAT expression may offer more detail on the biology of a patient’s cancer.
Future Considerations
The authors concluded that targeting LAT family transporters resulted in inhibition of growth factor and metabolic signaling pathways, inhibition in vivo of growth of prostate cancer tumors, and decreased expression of numerous genes associated with metastatic prostate cancer. The blockade of amino acid transporters, and leucine uptake, is an important potential tool in a field in need of additional mechanisms of treatment for castrate-resistant disease.
As our knowledge of the biology of castrate-resistant prostate cancer evolves, we will need to rely on identification and effective blockade of other pathways beyond the androgen receptor. Other than the multitargeted kinase inhibitor cabozantinib (Cometriq), there are few candidate pathway inhibitors under current investigation. Agents targeting the mTORC1 and PI3K pathways are in early-phase trials. While all data reported by Wang and colleagues are preclinical, inhibition of amino acid transporters is an exciting potential therapeutic target in prostate cancer. ■
Dr. Kessler is Assistant Professor in the Division of Medical Oncology, School of Medicine, University of Colorado Denver, Anschutz Medical Campus, and Dr. Crawford is Professor of Surgery and Radiation Oncology and Head of Urologic Oncology at the University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado.
Disclosure: Drs. Kessler and Crawford reported no potential conflicts of interest.
References
1. Wang Q, Tiffen J, Bailey CG, et al: Targeting amino acid transport in metastatic castration-resistant prostate cancer: Effects on cell cycle, cell growth, and tumor development. J Natl Cancer Inst 105:1463-1473, 2013.
2. Fuchs BC, Bode BP: Amino acid transporters ASCT2 and LAT1 in cancer: Partners in crime? Semin Cancer Biol 15:254-266, 2005.
3. Wang Q, Bailey CG, Ng C, et al: Androgen receptor and nutrient signaling pathways coordinate the demand for increased amino acid transport during prostate cancer progression. Cancer Res 71:7525-7536, 2011.
4. Noonan KL, North S, Bitting RL, et al: Clinical activity of abiraterone acetate in patients with metastatic castration-resistant prostate cancer progressing after enzalutamide. Ann Oncol 24:1802-1807, 2013.
5. Kaira K, Oriuchi N, Imai H, et al: Prognostic significance of L-type amino acid transporter 1 expression in resectable stage I-III nonsmall cell lung cancer. Br J Cancer 98:742-748, 2008.
