A new molecule, PH1, is attracting significant attention for its innovative approach in addressing a major hurdle in advanced prostate cancer: resistance driven by the androgen receptor splice variant 7 (AR-V7). PH1 is a spliceosome-modulating payload, delivered specifically to tumor cells via antibody-drug conjugates (ADC).
Preclinical studies using the 22Rv1 metastatic castration-resistant prostate cancer (mCRPC) model reveal that PH1 is capable of potently reducing AR-V7 receptor expression, a result that existing androgen receptor pathway inhibitors (ARPIs) such as enzalutamide and apalutamide cannot achieve.

Most patients with advanced prostate cancer eventually become resistant to ARPIs, often due to increased AR-V7 activity. In this setting, PH1 stands out by directly lowering the AR-V7 protein within resistant cancer cells, opening a therapeutic avenue for those with few remaining treatment options beyond chemotherapy.

Notably, PH1’s utility may not be limited to resistant disease. It also displays efficacy as a single agent in hormone-sensitive (ARPI-sensitive) prostate cancer models. Furthermore, when combined with first-line ARPIs, PH1 shows additive effects in laboratory models, suggesting a potential role both as first-line combination therapy and as a second-line option following ARPI resistance.

PH1 is delivered through ADCs such as AKTX-101, which uses a proprietary linker to release PH1 directly inside Trop2-positive tumor cells. Once inside, PH1 disrupts spliceosome function, causing production of mis-spliced proteins. This leads to cancer cell death and, importantly, also produces neoantigens that stimulate the immune system—a dual mechanism that is rare among existing ADC payloads.

Trop2 is widely recognized as a relevant and promising target in prostate cancer, particularly in advanced and treatment-resistant forms. It is a cell surface glycoprotein whose expression is significantly elevated in metastatic and castration-resistant prostate cancer compared to normal tissues.

The molecule is also designed to bypass cellular drug resistance mechanisms like efflux pumps, which can undermine many chemotherapeutic drugs. Preclinical results suggest PH1 ADCs not only induce direct tumor cell kill but may also enhance the efficacy and durability of immune checkpoint therapies.

Confirmation in clinical studies will be essential to determine its ultimate therapeutic value.

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