Novobiocin for Cancer

Recruiting at 21 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

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 All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 15

Duration: Up to 2 years

43 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial seeks to determine the safest and most effective dose of novobiocin sodium for treating certain types of cancer. Novobiocin blocks a protein that aids cancer cells in repairing damaged DNA, potentially stopping cancer growth. The trial targets individuals whose cancer has specific genetic mutations affecting DNA repair, particularly when standard treatments have failed. Eligible participants include those with advanced cancer and specific gene mutations who have not succeeded with other treatments. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the chance to be among the first to receive this potentially groundbreaking therapy.

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.

Is there any evidence suggesting that novobiocin sodium is likely to be safe for humans?

Research has shown that novobiocin is not linked to cancer or reproductive problems, indicating a positive safety profile. However, some warnings are important to note. Studies have found that novobiocin can cause allergic skin reactions and seriously irritate the eyes. It is also hazardous if swallowed or inhaled.

These findings suggest that while novobiocin carries some risks, it does not pose serious long-term safety issues like cancer or reproductive harm. Participants should avoid skin and eye contact and adhere to safety guidelines during the trial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard chemotherapy and targeted therapies for cancer, novobiocin sodium offers a fresh approach by potentially targeting cancer cells through a unique mechanism. Researchers are excited about novobiocin sodium because it interferes with the DNA repair process in cancer cells, which can lead to their death. This targeting method could provide a new way of attacking cancer cells, especially in cases where other treatments have failed. Additionally, its oral administration makes it more convenient for patients compared to some existing therapies that require intravenous delivery.

What evidence suggests that novobiocin might be an effective treatment for cancer?

Research has shown that novobiocin effectively kills cancer cells struggling to repair their DNA. One study demonstrated that novobiocin was highly effective at killing cells lacking the BRCA1 gene, crucial for DNA repair. This suggests that cancer cells, already impaired in DNA repair, may die when treated with novobiocin. Another study found that novobiocin targets and destroys cancer cells with a common genetic defect affecting DNA repair. These findings suggest that novobiocin, which participants in this trial will receive, might help shrink or stabilize tumors in people with certain genetic mutations. ^{6 7 8 9 10}

Who Is on the Research Team?

Geoffrey I. Shapiro

Principal Investigator

Dana-Farber - Harvard Cancer Center LAO

Are You a Good Fit for This Trial?

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

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Novobiocin Sodium

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.

How Is the Trial Designed?

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 tumor biopsy, medical imaging scans, and collection of blood samples throughout the trial.

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a Phase II trial involving 36 patients with non-small cell lung cancer, novobiocin was used alongside high-dose cisplatin, but only 8% of patients achieved a partial response, indicating limited efficacy in this setting.

The study suggested that the plasma levels of novobiocin were only about 50% of what is needed to enhance the effectiveness of cisplatin, implying that an intravenous formulation of novobiocin might be necessary for better results.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cisplatin and novobiocin in the treatment of non-small cell lung cancer. A Southwest Oncology Group study. Ellis, GK., Crowley, J., Livingston, RB., et al.[2019]

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]

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]

Citations

1. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2022-06608

Studying the Safety and Determining the Optimal Dose of ... This phase I trial tests the safety, side effects, and best dose of novobiocin in treating cancer patients with alterations in deoxyribonucleic acid (DNA) ...

2. withpower.com withpower.com/trial/phase-1-neoplasms-3-2023-e2f32

Novobiocin for Cancer · Recruiting Participants for Phase ... In a Phase II trial involving 36 patients with non-small cell lung cancer, novobiocin was used alongside high-dose cisplatin, but only 8% of patients achieved ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8224818/

A first-in-class Polymerase Theta Inhibitor selectively targets ... Among those, NVB had the highest efficacy in selectively killing the BRCA1−/− cells (Extended Data Fig. 4d). To demonstrate the cellular outcome of NVB exposure ...

4. dana-farber.org dana-farber.org/newsroom/news-releases/2021/antibiotic-novobiocin-found-to-kill-tumor-cells-with-dna-repair-glitch

Antibiotic Novobiocin found to kill tumor cells with DNA- ... An antibiotic developed in the 1950s and largely supplanted by newer drugs, effectively targets and kills cancer cells with a common genetic defect.

5. sciencedirect.com sciencedirect.com/topics/neuroscience/novobiocin

Novobiocin - an overview | ScienceDirect Topics Yang et al. reported that novobiocin sensitized BCRP overexpressing topotecan-resistant human breast carcinoma cells to topotecan and mitoxantrone [149].

6. cdn.caymanchem.com cdn.caymanchem.com/cdn/msds/18457m.pdf

Safety Data Sheet Chemicals known to cause cancer: Substance is not listed. · Chemicals known to cause reproductive toxicity for females: Substance is not listed.

7. neogen.com neogen.com/4a0fac/globalassets/pim/assets/original/10075/ncm4040-0.5_en-us_sds_v.2.0.pdf

Novobiocin Signal word (GHS US). : Warning. Hazard statements (GHS US). : H317 - May cause an allergic skin reaction. H319 - Causes serious eye irritation.

8. goldbio.com goldbio.com/documents/4953/N-451.pdf?srsltid=AfmBOorLavH6TN1YKGZcPw7UF0ngY7aMDV83f2-3dcn6F4LHt5I7E96P

N-451 Safety Data Sheet - Novobiocin Sodium Salt P280: Wear protective gloves/protective clothing/eye protection/face protection. P302+352: IF ON SKIN: Wash with soap and water.

9. file.medchemexpress.com file.medchemexpress.com/batch_PDF/HY-B0425A/Novobiocin-sodium-SDS-MedChemExpress.pdf

Novobiocin sodium-SDS-MedChemExpress 65 Components: This product does not contain any chemicals known to State of California to cause cancer, birth defects, or anyother reproductive harm.

10. imgcdn.mckesson.com imgcdn.mckesson.com/CumulusWeb/Click_and_learn/SDS_FSHSCI_SUPPLEMENT_ANTIMICROBIC_NOVOBIOCIN_AGAR_10ML_6PK.pdf

Safety Data Sheet Hazard-determining components of labeling: novobiocin sodium. · Hazard statements. H302+H332 Harmful if swallowed or if inhaled. · Precautionary ...