Recently, while in San Francisco for the AACR special conference on the PI3K-mTOR pathway in cancer, I was particularly struck by several important learnings that have since make me think more deeply about oncology drug development going forward:
- With targeted therapies, we need to more carefully select the patients, based on a clearly defined patient population
- We need to identify both the driving mutations and the adaptive pathway
- Aberrant activity is often also ligand driven
This means that in the future, targeted treatment may evolve in smaller subsets of disease with more logical double or even triple combinations. It also means that there will be more, smaller phase II trials with translational research incorporated, across multiple combinations to tease out the critical, defining protocol. Think more adaptive trial designs similar to the BATTLE and I-Spy series in lung and breast cancer, respectively.
Of course, Pharma’s immediate reaction is going to be “oh my, that’s going to be very expensive and difficult to do with novel-novels in clinical trials!”
The reality, however, is that it may not actually be sustainable to keep charging exhorbitant prices and smart companies with deep pockets and strong commitment will build portfolios with a wide range of different targets either in house, through licensing or acquisitions. The trend in this direction is slowly, but surely, happening as knowledge of the biology of different cancers and subsets improves.
It was therefore no surprise that two articles appeared last week in Science and Translational Medicine and piqued my interest. Goldstein, Zong and Witte (2011) provided some thoughtful commentary on research by Ateeq et al., (2011) on the SPINK1 mutation in prostate cancer. They observed:
The concept of one-size-fits-all therapeutics is becoming increasingly less relevant, because any one therapy is unlikely to be effective for all individuals with a complex disease such as cancer. For the hundreds of thousands of men who are diagnosed with prostate cancer each year, their tumors do not all share the same molecular machinery, pathways, or targets.
Ateeq et al., describe how SPINK1 contributes to the aggressive phenotype. Forced expression of recombinant SPINK1 increased prostate cancer cell proliferation and invasiveness, whereas knockdown of SPINK1 gene expression or treatment with a SPINK1-directed monoclonal antibody resulted in decreased cell division, invasiveness, and tumour growth.
SPINK1 is highly expressed in ~10% of prostate cancers, and expression has been correlated with aggressive disease.
Interestingly, SPINK1 mediated its neoplastic effects partly through interactions with the epidermal growth factor receptor (EGFR). Ateeq et al’s experiments showed that antibodies to both SPINK1 and EGFR blocked the growth of SPINK1+/ETS tumours more than either antibody alone, and did not affect SPINK1- tumours.
In the graphic below (courtesy of Goldstein et al., 2011), you can see that in part (a) SPINK1 secreted from prostate cancer cells can stimulate EGFR dimerization, phosphorylation, and downstream signaling through phosphoinositide 3-kinase (PI3K)/AKT, mitogen-activated protein kinase (MAPK), or janus kinase (JAK) pathways in an autocrine loop.
In part (b), in addition to small-molecule agents that block AR, PI3K/AKT, MAPK, or JAK signaling pathways, monoclonal antibodies against EGFR or SPINK1 could inhibit signal transduction by blocking the physical interaction between EGFR and the SPINK1 ligand:
In the research, an approved monoclonal antibody to EGFR, cetuximab, was used, together with an un-named SPINK1 antibody with better results than either alone. We should remember though, as Goldstein et al., note:
However, disappointing results in trials of EGFR-targeted therapies for prostate cancer with gefitinib, lapatinib, or cetuximab raise doubts about the importance of the EGFR signaling pathway for most prostate cancers.
What do these results mean?
Although animal research doesn’t always translate to positive results in humans in the clinic, it is entirely possible that better patient selection and the right combinations may be necessary to target a driving mutation, ligand and adaptive pathway in order to yield better results than previously seen with EGFR inhibitors.
Overall, I think this latest research does provide a solid rationale for the development of humanised anti-SPINK1 monoclonal antibodies for targeting a subset of patients with SPINK1 positive and ETS-negative prostate cancer in clinical trials. There are mouse antibodies available for research, but I couldn’t find a humanised one in development. It will be interesting to see any company takes up the challenge going forward.
Goldstein, A., Zong, Y., & Witte, O. (2011). A Two-Step Toward Personalized Therapies for Prostate Cancer Science Translational Medicine, 3 (72), 72-72 DOI: 10.1126/scitranslmed.3002169
Ateeq, B., Tomlins, S., Laxman, B., Asangani, I., Cao, Q., Cao, X., Li, Y., Wang, X., Feng, F., Pienta, K., Varambally, S., & Chinnaiyan, A. (2011). Therapeutic Targeting of SPINK1-Positive Prostate Cancer Science Translational Medicine, 3 (72), 72-72 DOI: 10.1126/scitranslmed.3001498