Andrea Miyahira: Hi, everyone. I'm Andrea Miyahira at the Prostate Cancer Foundation. Please welcome Dr. Di Zhao of MD Anderson Cancer Center. She will share her latest paper, CHD1 loss reprograms SREBP2-driven cholesterol synthesis to fuel androgen-responsive growth and castration resistance in SPOP-mutated prostate tumors, published in Nature Cancer. Dr. Zhao, thanks for joining.

Di Zhao: Yeah, thank you so much, Andrea. And it's my great pleasure to introduce our work here. And first, I would like to thank UroToday and Prostate Cancer Foundation for this great opportunity for me to present our work here which was recently published in Nature Cancer.

And technology has advanced our understanding of the world, including prostate cancer. And in the past two decades, the large scale cancer genomic studies have uncovered the genetic heterogeneity of prostate cancer and opened new avenues for identification of new molecular subtypes and the precision oncology.

There is an emerging subtype of prostate cancer characterized by SPOP mutations. And the previous studies have found that SPOP-mutated prostate cancer are more dependent on androgen. And several large scale clinical trials have shown that SPOP mutations are associated with improved survival outcomes after androgen deprivation therapy in prostate cancer patients.

It is notable that nearly half of the SPOP-mutated prostate tumors contain CHD1 deletions. However, it remains unclear how this CHD1 loss impacts this subtype. In these studies, we generated several genetically-engineered mouse models to calculate those different subtypes of prostate cancer with CHD1 deletion or SPOP mutation.

And our data demonstrate the combined CHD1 deletion and SPOP mutation can promote the prostate tumorigenesis, and CHD1 loss can confer the castration resistance in SPOP-mutated prostate cancer. By integrating the multi-omics approaches, we discovered a non-canonical function of CHD1 in repressing the SREBP2 gene expression, and which plays an essential role in regulating the cholesterol metabolism.

In CHD1-deficient prostate tumors, SREBP2 is overexpressed, which triggers the cholesterol biosynthesis. The increased cholesterol production was then transformed into an androgen and activated the androgen receptor to promote the tumor growth and castration resistance in SPOP-mutant prostate tumors.

Based on these mechanisms, we propose that inhibiting the cholesterol biosynthesis can resensitize the CHD1 deletion and SPOP-mutant prostate tumors to anti-androgen therapy. So atorvastatin is an FDA-approved cholesterol lowering drug. And in our 2D and 3D culture systems, we found synergistic effects between atorvastatin and abiraterone.

And most importantly, this combination showed significant anti-tumor effects in preclinical mouse models of castration-resistant prostate cancer with CHD1 deletion and SPOP mutation. So some taking home messages here include CHD1 deletion and SPOP mutations cooperate to promote prostate tumorigenesis. And CHD1 loss confers the castration in SPOP-mutant prostate cancer.

And the mechanistic studies showed that CHD1 reprograms the cholesterol metabolism by repressing SREBP2, and CHD1 loss-driven cholesterol production fuels androgen-responsive growth and the castration resistance in SPOP-mutant prostate tumors.

And our preclinical studies also demonstrate the combination of FDA-approved cholesterol lowering drugs, with anti-androgen therapy has therapeutic potential in prostate cancer-- in castration-resistant prostate cancer, especially those containing CHD1 deletion and SPOP mutation.

And at last, I would like to thank all the lab members and collaborators and all the funding support from different agencies, including Prostate Cancer Foundation. Thank you.

Andrea Miyahira: Thank you so much, Dr. Zhao, for sharing that. So do you know if the clinical outcomes of patients with prostate cancer with SPOP mutations who have versus don't have concurrent CHD1 deletion are any different? Like, for instance, they have differences in response to therapy, progression to CRPC, or other features.

Di Zhao: Yeah, that's a great question. So as I mentioned earlier, SPOP mutation has become an emerging predictive biomarker for anti-androgen therapy in clinics. Even though CHD1 has been frequently correlated with SPOP mutations, but unfortunately, its CHD1 status was not assessed in those large scale clinical studies due to the limitations of the genetic determination assays.

And to date, there is only one clinical study led by Dr. Johann de Bono. And they assessed the correlations between CHD1 status and anti-androgen response in men with castration-resistant prostate cancer. And they found that the CHD1 deletion presented a higher prevalence in castration-resistant prostate cancer, with about 17% compared to the patients with castration-sensitive prostate cancer, which has 15%.

And they also concluded that the CHD1 gene loci are driver events in SPOP-mutant prostate tumors development. And also don't [INAUDIBLE] to selection of castration. So I do believe those clinical observations align well with our findings in preclinical mouse models. And to demonstrate the role of CHD1 deletion confers the castration-resistance in SPOP-mutant prostate tumor.

Andrea Miyahira: OK. Thank you. And what possible therapeutic insights does your paper reveal? For instance, roles for targeting SREBP or how to treat patients with SPOP mutations with or without CHD1 loss.

Di Zhao: Yeah. I do believe our study provides some helpful therapeutic insights for the future clinical and preclinical studies. For example, our study suggests that using the SPOP mutation and CHD1 deletion, both of them as predictive biomarkers to predict which patients better respond to anti-androgen therapy or to predict the castration-resistance in prostate cancer patients.

And on the other hand, our studies also suggested to combine the cholesterol lowering medicines with abiraterone or other anti-androgen therapy in prostate cancer patients, especially those with CHD1 deletion. And of note, not only prostate cancer has CHD1 deletion, many other estrogen-dependent cancers, like endometrial cancer, oral cancer, and breast cancer, they also carry CHD1 deletion.

And I think the mechanisms we observed here in prostate cancer may also apply to other hormone-dependent cancer types. And that will further expand our study to other hormone-dependent prostate cancer therapy.

Andrea Miyahira: OK. And just to remind us, are CHD1 deletions always a subtype of SPOP mutations, or are they present in the absence of SPOP mutations or with other co-alterations?

Di Zhao: Yeah. Most of the CHD1 deletions co-occur with a SPOP mutation. But still there is a small amount of the CHD1 deletions showed up in SPOP wild-type prostate tumors. However, in other cancer types, SPOP mutation is not that driver event or that common.

So in those kind of estrogen-dependent cancers, CHD1 loss could be a more independent genetic event. But further studies need to examine whether CHD1 deletion may co-occur with other ER or estrogen receptors and all their regulators at the genetic level.

Andrea Miyahira: OK, thank you. And as you found that CHD1 loss increases cholesterol metabolism, do you think other patient factors could influence these pathways, such as obesity or diet?

Di Zhao: Yeah, that's a great idea. So I do think that obesity or high cholesterol diet may supply cholesterol and facilitate androgen production in prostate cancer cells. And also those high cholesterol diets may have a more profound impact on promoting SPOP-mutant prostate tumors.

So I think that management should be considered for those patients with SPOP mutation particularly. And of course, our studies, we don't have evidence to show that, but I do think further studies are needed to really substantiate this hypothesis.

Andrea Miyahira: OK, thank you. And what are your next steps, and do you have any translational plans?

Di Zhao: Yeah, sure. Because both of these drugs have been FDA approved and has been used in patients, and also some clinical trials are ongoing to test this combination in prostate cancer. So I do believe there is a very significant translational potential of our studies.

So our next step, we plan to validate the associations of CHD1 deletion with castration-resistance in clinical samples because previously, large scale clinical trials have already provided all these samples available, and it's important to determine CHD1 status in those samples.

And also, our team, we'll also actively collaborate with clinicians at MD Anderson and other institutes and also the industries who design-- who has the cholesterol lowering drugs and-- who has developed the cholesterol lowering drugs. And to design the novel clinical trials and test the combination of these abiraterone with cholesterol lowering medicines in prostate cancer patients.

And most importantly, to use CHD1 and SPOP as biomarkers to follow patient selection. And follow mechanistic studies. And in my current lab, we're also continuing working on the mouse model we established in this study and try to identify more therapeutic vulnerabilities for this subtype.

Andrea Miyahira: OK. Well, thank you so much, Dr. Zhao, for sharing the study with us.

Di Zhao: Yeah. Thank you, Andrea.