Abstract
Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma with a 95% mortality rate with no improvement to treatment in decades, and new therapies are desperately needed.
PEN-221 is a miniaturized peptide-drug conjugate (∼2 kDa) designed to target SCLC via a Somatostatin Receptor 2 (SSTR2)-targeting ligand and to overcome the high proliferation rate characteristic of this disease by using the potent cytotoxic payload, DM1. SSTR2 is an ideal target for a drug conjugate, as it is overexpressed in SCLC with limited normal tissue expression.
In vitro, PEN-221 treatment of SSTR2-positive cells resulted in PEN-221 internalization and receptor-dependent inhibition of cellular proliferation.
In vivo, PEN-221 exhibited rapid accumulation in SSTR2-positive SCLC xenograft tumors with quick clearance from plasma.
Tumor accumulation was sustained, resulting in durable pharmacodynamic changes throughout the tumor, as evidenced by increases in the mitotic marker of G2-M arrest, phosphohistone H3, and increases in the apoptotic marker, cleaved caspase-3.
PEN-221 treatment resulted in significant antitumor activity, including complete regressions in SSTR2-positive SCLC xenograft mouse models. Treatment was effective using a variety of dosing schedules and at doses below the MTD, suggesting flexibility of dosing schedule and potential for a large therapeutic window in the clinic.
The unique attributes of the miniaturized drug conjugate allowed for deep tumor penetration and limited plasma exposure that may enable long-term dosing, resulting in durable tumor control.
Collectively, these data suggest potential for antitumor activity of PEN-221 in patients with SSTR2-positive SCLC.
See also:
- Official Web Site: The Di Bella Method;
- Somatostatin in oncology, the overlooked evidences - In vitro, review and in vivo publications;
- Publication: Over-Expression of GH/GHR in Breast Cancer and Oncosuppressor Role of Somatostatin as a Physiological Inhibitor (from Di Bella's Foundation);
- Publication: The Entrapment of Somatostatin in a Lipid Formulation: Retarded Release and Free Radical Reactivity (from Di Bella's Foundation);
- The Di Bella Method (A Fixed Part - Bromocriptine and/or Cabergoline);
- The Di Bella Method (A Fixed Part - Calcium, 2 grams per day, orally);
- Complete objective response to biological therapy of plurifocal breast carcinoma;
- Pancreatic Adenocarcinoma: clinical records on 17 patients treated with Di Bella's Method;
- Oesophageal squamocellular carcinoma: a complete and objective response;
- Neuroblastoma: Complete objective response to biological treatment;