26 March 2020 - - US-based clinical-stage biopharmaceutical company Scholar Rock (NASDAQ: SRRK) has announced the publication in the peer-reviewed journal Science Translational Medicine of preclinical data that established the therapeutic rationale for evaluating a potent and highly selective inhibitor of transforming growth factor-beta 1 (TGFβ1) activation to overcome primary resistance to checkpoint inhibitor therapy.

The introduction of immunotherapy, including checkpoint inhibitor therapy, has revolutionized the treatment of a wide variety of cancers, delivering profound and durable responses for many patients. Unfortunately, this therapeutic approach is only effective in a small subset of patients; even at the outset of treatment, some tumors show primary resistance to anti-PD-(L)1.

Human tumor profiling and several preclinical studies have implicated TGFβ signaling activity as a potential point of intervention to overcome primary resistance to checkpoint inhibition.

However, the development of therapies targeting TGFβ signaling has been hindered by dose-limiting cardiotoxicities, potentially due to non-selective inhibition of multiple TGFβ isoforms.

As detailed in the Science Translational Medicine publication "Selective inhibition of TGFβ1 activation overcomes primary resistance to checkpoint blockade therapy by altering tumor immune landscape," SRK-181 inhibits TGFβ1 activation with high selectivity and has demonstrated in preclinical studies the potential to overcome primary resistance and meaningfully expand the number of patients who could benefit from checkpoint inhibitor therapy. (Martin et al., Sci. Transl. Med. 12:25 March 2020)

Based on RNAseq data from the Cancer Genome Atlas, TGFβ1 is the most prevalent isoform expressed in the majority of human cancer types, with the exception of breast cancer, mesothelioma, and prostate cancer, where TGFβ3 is also expressed.

This finding was also observed in examination of individual samples.

TGFβ1 is likely expressed by multiple cell types within the tumor microenvironment and each cell type produces TGFβ1 in different large latent complexes.

This is supported by TCGA data, which indicates essentially all tumor types express mRNA encoding all four LLC-presenting molecules, namely LTBP1, LTBP3, GARP, and LRRC33.

By targeting the precursor form of TGFβ1, SRK-181 achieves exquisite isoform specificity, inhibiting latent TGFβ1 activation in all known molecular contexts without binding to latent TGFβ2, latent TGFβ3, or any of the three active TGFβ growth factors.

Scholar Rock identified three syngeneic mouse tumor models that recapitulate key features of human primary resistance to checkpoint inhibitor therapy: MBT-2 (bladder cancer), Cloudman S91 (melanoma) and the EMT-6 (breast cancer) mouse models.

Combination treatment with SRK-181-mIgG1 and an anti-PD-1 therapy resulted in tumor regression or control and survival benefit across these three identified cancer models. This tumor response was also shown to be durable, where mice with no measurable tumor at treatment cessation remained tumor free.
 
Scholar Rock is a clinical-stage biopharmaceutical company focused on the discovery and development of innovative medicines for the treatment of serious diseases in which signaling by protein growth factors plays a fundamental role.