Novobiocin for Cancer

Recruiting at17 trial locations

Overseen by Geoffrey I. Shapiro

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: National Cancer Institute (NCI)

Must be taking: Parp inhibitors

Must not be taking: CYP3A4/5 inhibitors, QTc prolongation drugs

Disqualifiers: Chemotherapy, Radiotherapy, Gilbert syndrome, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This trial tests novobiocin, an antibiotic, in cancer patients with specific DNA repair gene mutations who haven't responded to other treatments. Novobiocin blocks a protein that helps cancer cells repair themselves, leading to their death. Studies show that novobiocin can make other cancer treatments more effective.

Do I need to stop taking my current medications for the trial?

The trial requires that you stop taking certain medications, specifically those that are strong inhibitors or inducers of CYP3A4/5, substrates of certain transport proteins, or those that prolong the QT interval. You should consult with your doctor to review your current medications and see if any need to be stopped before joining the trial.

How does the drug Novobiocin Sodium differ from other cancer treatments?

Novobiocin Sodium is unique because it targets the Hsp90 protein, which is involved in cancer cell growth, and it can enhance the effectiveness of other cancer drugs by making cancer cells more sensitive to them. Unlike many standard treatments, it also has the potential to work in combination with other agents to inhibit cancer cell growth more effectively. ^{1 2 3 4 5}

Research Team

Geoffrey I. Shapiro

Principal Investigator

Dana-Farber - Harvard Cancer Center LAO

Eligibility Criteria

This trial is for adults with advanced or inoperable tumors that have specific mutations in DNA repair genes. Patients must have tried other treatments without success and may or may not have used PARP inhibitors, depending on the type of cancer. They should be relatively healthy otherwise, with adequate blood cell counts and organ function.

Inclusion Criteria

Any number of prior therapy regimens is allowed.

Platelets >= 100,000/mcL

Patients must have histologically confirmed malignancy that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive novobiocin sodium orally once daily for 5 days in a row followed by 2 days off each week. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

Up to 2 years

Biopsies at baseline, day 15 of cycle 1, and at time of progression; imaging every 8 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

Every 3-6 months for 2 years

Treatment Details

Interventions

• Novobiocin Sodium (Antibiotic)

Trial Overview The trial is testing Novobiocin Sodium's safety and optimal dosage. It's an antibiotic thought to kill cancer cells by blocking a protein involved in DNA repair. The study includes biopsies, biospecimen collection, and diagnostic imaging to monitor effects.

Participant Groups

Group I: Treatment (novobiocin sodium) Experimental Treatment 4 Interventions

Patients receive novobiocin sodium PO QD for 5 days in a row followed by 2 days off each week. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo a tumor biopsy at baseline, on day 15 of cycle 1, and at time of progression. Patients undergo medical imaging scans at baseline and every 8 weeks. Patients also undergo blood sample collection on study.

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Dr. Douglas R. Lowy

National Cancer Institute (NCI)

Chief Executive Officer since 2023

MD from New York University School of Medicine

Dr. Monica Bertagnolli

National Cancer Institute (NCI)

Chief Medical Officer since 2022

MD from Harvard Medical School

Findings from Research

Novobiocin effectively inhibits the proliferation of B16 melanoma cells, with this effect being reversible once the drug is removed, indicating a potential for controlled treatment.

In vivo studies in mice showed that repeated doses of novobiocin slowed tumor growth, and when combined with other agents, it enhanced the anti-tumor effects, suggesting its potential as a valuable component in melanoma therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novobiocin-induced anti-proliferative and differentiating effects in melanoma B16. Nordenberg, J., Albukrek, D., Hadar, T., et al.[2019]

Hsp90 is a key target for cancer treatment, and novobiocin is the first identified inhibitor that targets its C-terminal region, showing promise in cancer therapy.

Among the tested analogues of novobiocin, compound 37j demonstrated the strongest anti-proliferative effects on breast cancer cell lines and effectively induced the degradation of Hsp90-dependent client proteins at very low concentrations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novobiocin analogues with second-generation noviose surrogates. Zhao, H., Blagg, BS.[2021]

Novobiocin, a natural product that inhibits Hsp90, has been modified to create analogs with either anti-cancer or neuroprotective properties, depending on the structure of the amide side chain.

Short alkyl or cycloalkyl amide side chains lead to neuroprotective effects, while longer chains (five or more carbons) are associated with anti-cancer activity by disrupting Hsp90 interactions and promoting the degradation of client proteins.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Diverging Novobiocin Anti-Cancer Activity from Neuroprotective Activity through Modification of the Amide Tail. Ghosh, S., Liu, Y., Garg, G., et al.[2020]

Novobiocin significantly enhances the toxicity of topotecan and mitoxantrone in breast cancer cells that have developed resistance, specifically in MCF7/TPT300 cells.

The mechanism by which novobiocin works involves increasing the accumulation of topotecan in these resistant cells and inhibiting its efflux, suggesting it could be a potential treatment to overcome drug resistance in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novobiocin sensitizes BCRP/MXR/ABCP overexpressing topotecan-resistant human breast carcinoma cells to topotecan and mitoxantrone. Yang, CH., Chen, YC., Kuo, ML.[2018]

References

1. England pubmed.ncbi.nlm.nih.gov

Novobiocin-induced anti-proliferative and differentiating effects in melanoma B16. [2019]

2. England pubmed.ncbi.nlm.nih.gov

Novobiocin analogues with second-generation noviose surrogates. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

Cisplatin and novobiocin in the treatment of non-small cell lung cancer. A Southwest Oncology Group study. [2019]

4. United States pubmed.ncbi.nlm.nih.gov

Diverging Novobiocin Anti-Cancer Activity from Neuroprotective Activity through Modification of the Amide Tail. [2020]

5. Greece pubmed.ncbi.nlm.nih.gov

Novobiocin sensitizes BCRP/MXR/ABCP overexpressing topotecan-resistant human breast carcinoma cells to topotecan and mitoxantrone. [2018]