Two Novel Genes May Open New Precision Treatment Possibilities in Metastatic Colorectal Cancer

As treatment strategies for metastatic colorectal cancer shift to be more tailored, investigations assessing the predictive value of novel gene biomarkers such as monoamine oxidase B (MAOB) and CDC37 have become more important than ever, according to Heinz-Josef Lenz, MD.

Lenz, a professor of medicine and J. Terrence Lanni Chair in Gastrointestinal Cancer Research at Keck School of Medicine as well as co-director of both the Center for Molecular Pathway and Drug Discovery and the Norris Center for Cancer Drug Development of University of Southern California (USC), was senior author on a study analyzing patient data from the phase 3 CALGB (Alliance)/SWOG 80405 trial (NCT00265850) examining the predictive value of MAOB and CDC37 gene expression for targeted therapeutics in metastatic CRC.^1,2

Results from the analyses were presented at the 2022 American Society of Clinical Oncology Annual Meeting and indicated that patients with low MAOB gene expression derived a stronger benefit from cetuximab (Erbitux)–based regimens vs higher expression levels. Moreover, patients with CDC37-dependent tumors could achieve more benefit from regorafenib (Stivarga) and bevacizumab (Avastin), as both agents target heat shock protein 90 (HSP90) client kinases or signaling pathways.

“Many [clinicians] are probably not familiar with these 2 genes. I hope that [the community] may realize that using new technologies, such as transcriptome analysis, could be a new important tool that we need to use more to find better targets or better predictive and prognostic markers.”

In an interview with CancerNetwork^®, Lenz detailed the value of novel molecular targets and highlighted where future research efforts need to be focused to continue positively impacting precision medicine in this population.

CancerNetwork^®: Start by discussing the rationale for assessing the predictive value of MAOB in CRC?

Lenz: We investigated the expression level of MAOB in metastatic colon cancer. The expression level of this gene is known to be associated with poor prognosis in patients with CRC. It plays a big role in the epithelial-to-mesenteric transition, which is a critical step for metastases. Now, there is a very interesting connection because MAOB also plays a role in Parkinson disease as well as neurodegenerative diseases. We have seen that patients with Parkinson disease seem to be protected from developing CRC. We were very interested to see how the gene expression would be potentially prognostic and predictive. Now, we use the clinical SWOG 8045 trial, which is a first-line [study of] metastatic CRC comparing cetuximab, an EGF receptor–based treatment, vs bevacizumab, an anti–VEGF-based treatment.

We looked for patients who had high, moderate, or low expression levels and for clinical outcomes. What we saw was very interesting and unexpected. We didn’t see any differences in outcome for high and low expression in patients treated with bevacizumab and chemotherapy but we saw a significant difference in progression-free survival and overall survival with cetuximab. High expression levels of MAOB [were] associated with poor outcomes and the low [expression group] had a significant prolongation of overall survival. In fact, [it] more than doubled.

It’s very interesting to see but the relationship between this particular gene that plays a role in neurodegenerative diseases could impact the efficacy of EGF receptor inhibitors. We don’t fully understand the relationship, we only are aware of the EMT transition role of MAOB and the EGF receptor. But when we also looked for the differences between men and women, we were completely surprised. The difference is only seen in men. [Although] we do not fully understand that particular subset, the differences are very large, from a median survival of 17 months to 40 months. [This is] very clinically meaningful. This, of course, has triggered additional studies where we [may] better understand the role of MAOB. Interestingly, there are inhibitors of this gene in the treatment of neurodegenerative diseases, giving us potential treatment options for patients with high expression and [insight into] whether this may actually impact the outcome of this patient population.

Could you touch on the role of CDC37 in metastatic CRC?

We were very interested in CDC37. It’s a very interesting protein [in terms of] its function. It’s a cochaperone of [HSP90], so it’s not a very commonly used gene or target. [However], HSP90 plays a big role in the stabilization of protein kinases. Some of them are important for patients with colorectal cancer, such as the VEGF or FGF receptor. It does not play a role in stabilization of the EGF receptor.

The differential benefit of HSP90 co-chaperoning with CDC37 could be a potential marker for efficacy of anti VEGF treatment and not EGF receptor antibodies. That was our hypothesis. We again used the 8045 clinical trial, which has the benefit of a side-by-side comparison of cetuximab and bevacizumab with chemotherapy in first-line metastatic colon cancer. What we found was what we hypothesized: that patients [achieved] high benefit from anti-VEGF treatment but not from cetuximab. This is a very interesting distinction. To really validate the potential benefit of anti-VEGF treatment, we also had access to a clinical trial using regorafenib, a multi-kinase inhibitor with a major focus of VEGF receptor kinases. It showed the same benefit. [Patients with] high expression benefited from anti-VEGF strategies, indicating that CDC37 in combination with HSP90 plays a significant role in anti-VEGF therapies.

What do you feel is the promise of these 2 targets for this patient population?

Particularly MAOB [holds promise] because there are inhibitors used for neurodegenerative diseases that would give us access to new treatment opportunities. We are planning to [test] that in preclinical mouse models. For CDC37 and HSP90, there are inhibitors of the heat shock protein that may not be as established as the inhibitors of MAOB. But there are ways to potentially interfere with the expression level of this chaperone protein. So yes, I think these are potential targetable new proteins that may impact the efficacy of our current chemotherapeutic regimens.

Where should research in molecular markers be focused to move the needle forward for patients with CRC?

With the development of more cutting-edge technologies that allow us to apply next-generation sequencing, one of the things we need to do in the future is transcriptome analysis. These 2 abstracts clearly demonstrate that looking at gene expression levels give us potentially new insights of potential targets, and not only mutations, but the expression level of these genes may play a critical role and help us to find patients who benefit more from certain targeted agents than others.

References

1. Zhang W, Millstein J, Yang Y, et al. Predictive value of MAOB gene expression for targeted therapy in patients (pts) with metastatic colorectal cancer (mCRC) enrolled in CALGB (Alliance)/SWOG 80405. J Clin Oncol. 2022;40(suppl 16):3580. doi:10.1200/JCO.2022.40.16_suppl.3580
2. Arai H, Yang Y, Millstein J, et al. Predictive value of CDC37 gene expression for targeted therapy in metastatic colorectal cancer (mCRC). J Clin Oncol. 2022;40(suppl 16):3586. doi:10.1200/JCO.2022.40.16_suppl.3586