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Clinical update: novel targets in gynecologic malignancies

Carol Aghajanian1

  • 1Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.

Seminars in Oncology
|April 1, 2005
PubMed

Insights

Bortezomib, a proteasome inhibitor, shows promise in treating chemotherapy-resistant ovarian cancer by blocking nuclear factor-kappa B (NF-kappaB). Combination therapy with carboplatin yielded significant responses in a Phase I trial.

Area of Science:

  • Oncology
  • Pharmacology
  • Cancer Biology

Background:

  • Bortezomib is a proteasome inhibitor effective against chemotherapy-resistant tumors, notably multiple myeloma.
  • Nuclear factor-kappa B (NF-kappaB) activation is implicated in tumor cell survival and chemoresistance, particularly in ovarian cancer treated with platinum agents.
  • Platinum-based chemotherapy (e.g., cisplatin) is a first-line treatment for ovarian cancer, but resistance can develop.

Purpose of the Study:

  • To evaluate the safety and efficacy of bortezomib in solid tumors, including ovarian cancer.
  • To determine if bortezomib can overcome chemoresistance by inhibiting NF-kappaB.
  • To assess the potential of combining bortezomib with platinum-based chemotherapy in ovarian cancer patients.

Main Methods:

  • Summary and examination of two Phase I clinical trials involving bortezomib.
  • Trial 1: Single-agent bortezomib in advanced malignancies.
  • Trial 2: Combination of bortezomib with carboplatin in ovarian cancer patients, focusing on NF-kappaB inhibition.

Main Results:

  • Single-agent bortezomib was found to be safe and manageable in advanced solid tumors, with potential efficacy.
  • In the combination trial, seven out of nine ovarian cancer patients experienced major responses to bortezomib and carboplatin.
  • Bortezomib demonstrated the ability to inhibit NF-kappaB, a key factor in chemoresistance.

Conclusions:

  • Bortezomib shows promising results as a single agent in solid tumors and in combination therapy for recurrent ovarian cancer.
  • The inhibition of NF-kappaB by bortezomib may overcome platinum resistance in ovarian cancer.
  • Further clinical investigation is warranted to confirm these findings and establish optimal treatment strategies.

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