DIAPH3 Predicts Breast and Prostate Cancer Responses to Chemotherapies

Michael Freeman, PhD

Michael Freeman, PhD

A publication inScientific Reportshas identified a novel biomarker, diaphanous-related formin-3 (DIAPH3), which may help predict response to taxane-based chemotherapies in patients with metastatic breast or prostate cancer.¹According to the researchers, these findings may help improve selection of patients that would benefit most from these therapies.

“This proof-of-principle study showed that it is possible to perform a phenotypical analysis of cancer cells that have certain characteristics and behaviors,” said senior author Michael Freeman, PhD, vice chair of research in the Cedars-Sinai Department of Surgery, in an interview withTargeted Oncology. “We can identify vulnerabilities in those cells, which we could potentially [target] in a clinical situation.”

Invasive tumors are often characterized by amoeboid behavior, which contributes to metastasis by increasing the deformability of the cells²and improving their survival in the vasculature.³DIAPH3 is a protein involved in mechanisms that increase cell rigidity and thereby reduce amoeboid behavior, and loss of DIAPH3 is prevalent in the tumors of patients with metastatic disease.⁴

Freeman et al showed that low intratumoral DIAPH3 was associated with poorer overall survival in cohorts of patients with prostate cancer and glioblastoma, respectively, suggesting that DIAPH3 loss “may be of clinical significance and relevant to patient prognosis.” Furthermore, the researchers showed that in vitro silencing of DIAPH3 in breast and prostate cancer cell lines altered microtubule architecture and stability, causing the cells to be more deformable.

“[The cells] can squeeze through tissue spaces and are more migratory,” said Freeman. “The tumor cells are more invasive…and are able to move into the circulation.”

Freeman also indicated that these highly deformable cells readily shed bioactive tumor-derived particles that may even contain DNA. These particles can travel to other sites in the body through the circulation and prepare premetastatic niches, microenvironments containing tumor cells and factors that facilitate eventual growth of the metastatic tumor. Freeman stated that understanding the genetic characteristics and associated phenotypic behavior of the amoeboid-like tumor cells is important for development of future therapies and for identifying who will benefit from them.

“Using [advanced molecular] methods to identify genetic signatures of the amoeboid phenotype will provide deeper insight into development of directed therapies for patients,” he said.

Although neoadjuvant chemotherapy with taxanes improves outcomes for metastatic breast and prostate cancers, response to treatment varies considerably among patients. Freeman et al showed that in vitro silencing of DIAPH3 increased sensitivity to paclitaxel, docetaxel, and epothilone B in breast and prostate cancer cell lines, suggesting that loss of the gene may predict tumor response to taxane-based chemotherapy.

Indeed, previous studies in human trials have shown that genetic signatures predict outcomes following taxane-based neoadjuvant chemotherapy.^5,6The researchers in the present study analyzed gene expression profiles from three randomized clinical trials and similarly showed that patients with breast cancer and low intratumoral DIAPH3 levels had a greater response to taxane-based neoadjuvant chemotherapy. According to Freeman, fine-tuning of these biomarker signatures will likely help optimize selection of chemotherapy for metastatic disease.

“We might be able to identify [whether a patient has an amoeboid-type tumor] if we had a significantly robust genetic signature,” said Freeman. “[The tumors] have vulnerabilities, and we can find those vulnerabilities and exploit them [with therapies].”

Identification of precise genetic signatures may also help screen patients who might benefit from taxane-based chemotherapy in the early stages of disease. Freeman indicated that some primary breast cancers show focal loss of DIAPH3, and identifying genetic signatures may help target lesions that form earlier in the disease course.

“We think DIAPH3 is very significantly involved in [the tumor] sensitivity to taxane,” said Freeman. “If there are ways to identify the lesion earlier in the disease course, we might be able to prophylactically apply taxanes to achieve clinical benefit.”

According to Freeman, several researchers are investigating a precision medicine approach in which possible therapy combinations are designed specifically for an individual’s tumor, accounting for cancer subtype and stochastic elements within the tumor itself. However, he indicated this approach can be particularly challenging, especially for metastatic disease.

“There are limitations with sampling, understanding what we’re looking at, and interpreting it in the context of an individual person,” said Freeman. “The question is how to design a therapy for an individual that takes into account the genotype and expressed genotype of the specific type of tumor. We’re still in the early stages of precision medicine as it applies to cancer.”

However, he emphasized that identifying biomarkers that contribute to the amoeboid phenotype can help narrow the group of patients who will likely benefit from taxane-based therapies. Furthermore, the authors indicated future studies that identify amoeboid cells in vivo and elucidate their vulnerabilities to chemotherapies will help improve development of novel therapeutic options.

“By identifying cancer biomarkers, then customizing treatment plans for individuals based on this genetic information, we can greatly improve the effectiveness of cancer therapies," said Shlomo Melmed, MD, senior vice president of academic affairs and director of the Burns and Allen Research Institute at Cedars-Sinai Medical Center, in a press release.⁷“This customized plan replaces a one-size-fits-all approach to cancer treatment.”

References:

1. Morley S, You S, Pollan S, et al. Regulation of microtubule dynamics by DIAPH3 influences amoeboid tumor cell mechanics and sensitivity to taxanes.Sci Rep. 2015 Jul 16;5:12136. doi: 10.1038/srep12136.

2. Sahai E, Marshall CJ. Differing modes of tumour cell invasion have distinct requirements for Rho/ROCK signalling and extracellular proteolysis.Nat Cell Biol. 2003;5(8):711-719.

3. Soon L, Braet F, Condeelis J. Moving in the right direction-nanoimaging in cancer cell motility and metastasis.Microsc Res Tech. 2007 Mar;70(3):252-257.

4. Hager MH, Morley S, Bielenberg DR, et al. DIAPH3 governs the cellular transition to the amoeboid tumour phenotype.EMBO Mol Med. 2012 Aug;4(8):743-60. doi: 10.1002/emmm.201200242.

5. Esserman LJ, Berry DA, Cheang MC, et al. Chemotherapy response and recurrence-free survival in neoadjuvant breast cancer depends on biomarker profiles: results from the I-SPY 1 TRIAL (CALGB 150007/150012; ACRIN 6657).Breast Cancer Res Treat. 2012 Apr;132(3):1049-62. doi: 10.1007/s10549-011-1895-2.

6. Hatzis C, Pusztai L, Valero V, et al. A genomic predictor of response and survival following taxane-anthracycline chemotherapy for invasive breast cancer.JAMA. 2011;305(18):1873-1881. doi: 10.1001/jama.2011.593.

7. Cedars-Sinai Medical Center. New biomarker identified in breast and prostate cancers holds promise for treating disease. Available athttp://cedars-sinai.edu/About-Us/News/News-Releases-2015/New-Biomarker-Identified-in-Breast-and-Prostate-Cancers-Holds-Promise-for-Treating-Disease.aspx. Accessed August 17, 2015.