FTase Inhibition Holds Promise for RAS Targeting and Beyond

William Pass, DVM
Published: Tuesday, May 15, 2018
The study is currently ongoing with 2 other patient cohorts, including a group of patients with HRAS-mutant thyroid carcinoma and a group of patients with squamous cell carcinoma not of the head and neck.7

Tipifarnib May Target CXCL12/CXCR4

Previous studies’ results have shown that tipifarnib can generate major responses in some patients with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML), but the overall activity and molecular mechanisms behind these responses has remained unclear. Although this mystery has thus far precluded drug registration, recent research suggests that tipifarnib may target the CXCL12/CXCR4 pathway.9

The CXCL12 (stromal cell-derived factor-1)/ CXCR4 (CXC receptor 4) axis plays a part in a variety of neoplastic events, including metastasis, survival, and angiogenesis. As a homeostatic chemokine, CXCL12 controls secondary lymphoid tissue architecture and hematopoietic cell trafficking. CXCR4 activity is thought to involve the RAS-activated signaling pathway, although exact mechanisms are unknown. CXCR4 is broadly expressed on hematopoietic cells such as B lymphocytes, T lymphocytes, CD34-positive hematopoietic stem cells (HSCs), macrophages, monocytes, eosinophils, and neutrophils. Further expression of CXCR4 can be found on colon, lung, heart, brain, liver, kidney, epithelial, endothelial, and some progenitor cells. Functional CXCR4 is expressed on several types of tissue-committed stem cells and embryonic pluripotent stem cells, allowing them to invade and/or migrate along CXCL12 gradients.10

Previous research has found that CXCL12/ CXCR4 signaling causes the bone marrow to retain neoplastic cells, which protects them from apoptosis. Findings from clinical trials in patients with multiple myeloma and non- Hodgkin lymphoma showed that treatment with plerixafor, a small molecule inhibitor of CXCR4, prompted cellular egress from bone marrow, thereby increasing collection yield for later HSC transplant. Additionally, a mouse model of acute promyelocytic leukemia revealed that treatment with a CXCR4 antagonist improved the efficacy of cytarabine, as bone marrow protection was lost when neoplastic cells were released into circulation. These findings affirm that increased CXCL12/CXCR4 causes cell retention in the bone marrow, making it an attractive target in bone marrow neoplasia.

In a 2014 study involving patients with AML, treatment with tipifarnib at 300 mg twice daily for 3 weeks led to response rates of up to 20%.11 However, patient-specific responses could not be correlated with blast karyotype, clinical features, FTase inhibition, or RAS mutation status. With regard to this finding, the researchers noted that a reliable predictor of response to tipifarnib was still lacking.

Fortunately, Antonio Gualberto, MD, PhD, and his team at Kura Oncology, Inc. may be closing in on an answer. In recent findings presented at the 2017 American Society of Hematology Annual Meeting, investigators showed that tipifarnib may target the CXCL12/CXCR4 pathway.9 In patients with AML and MDS, tipifarnib was most effective when high levels of CXCL12 were found in the bone marrow. The researchers concluded that a high level of CXCR4 compared with a low level of the antagonistic receptor CXCR2 may serve as a reliable biomarker for tipifarnib in bone marrow neoplasia.

In a group of 58 patients with relapsed or refractory AML who were treated with tipifarnib, the quintile expressing the highest CXCR4/CXCR2 ratios achieved progression-free survival (PFS) times nearly double those of all other patients (57 days vs 29 days; P = .026). When tipifarnib was administered to another cohort of 15 patients with chronic myelomonocytic leukemia, the tertile with the highest CXCR4/CXCR2 ratios achieved a PFS of 280 days compared with 84 days for those with lower levels (P = .015).

“Analysis of CXCR4 and CXCR2 expression in bone marrow aspirates of mononuclear cells revealed an association between the ratio of CXCR4 to CXCR2 and the clinical activity of tipifarnib,” investigators reported. This correlation “was consistent across endpoints, clinical settings, and indications,” they added. Ongoing phase II clinical trials aim to elucidate these findings by researching upstream and downstream farnesylated targets in the CXCL12/CXCR4 pathway.

The researchers noted that tipifarnib has a safety profile at least as favorable as best supportive care including hydroxyurea. With older and more frail patients with AML, tipifarnib could be a more attractive option than chemotherapy, particularly when a high CXCR4/CXCR2 ratio is detected.

The Future of FTIS

Although combination therapies have yielded mixed results, FTIs may increase sensitivity to chemotherapeutics or radiation with appropriate timing, particularly in HRAS-mutant cancer types.5 In light of the recent successes with tipifarnib in HRAS-mutant HNSCC, more combination studies may be forthcoming. Kura Oncology, a biopharmaceutical company headquartered in San Diego, California, has 4 ongoing clinical trials investigating tipifarnib in HNSCC and myeloid malignancies (Table).

Following a meeting with the FDA, the company said it plans to initiate a registration- directed phase II trial in patients with HRAS-mutant HNSCC in the second half of 2018. The single-arm study, to be called AIM-HN, would seek to enroll at least 59 patients with recurrent or metastatic disease.12

At press time, tipifarnib remains the only FTI undergoing clinical trials for use in cancer treatment, while previously investigated FTIs BMS-214662, CP-609,754, and AZD3409 remain dormant, according to a search of the ClinicalTrials.gov website. Outside of the cancer arena, however, research with other FTIs continues.

Of note, lonafarnib is undergoing clinical trials for Hutchinson-Gilford Progeria Syndrome (HGPS), a terminal illness that causes premature aging. In patients with HGPS, progerin is the protein thought to be responsible for blocking normal cell function, and as farnesylation is required for progerin activity, lonafarnib could be the first therapeutic drug for this rare disease. Completed trials have recorded increased survival times in treated patients.13

To date, more than 50 proteins are known to undergo posttranslational farnesylation, and additional activity may be elucidated in the future. Further research is needed to better understand associated pathways. As early trials using FTIs to indirectly target the RAS pathway are found, blocking farnesylation is inadequate as a therapeutic strategy for all tumors with RAS mutations.

However, ongoing research shows that HRAS-mutant varieties appear susceptible to tipifarnib due to a lack of redundant enzymes. Along the same optimistic lines, research into the CXCL12/CXCR4 pathway is defining which patients with hematological malignancies are likely to respond to FTI therapy and illuminating associations with the RAS pathway. As research clarifies the complex network of pathways that drive neoplasia and other diseases, more patient-specific therapies may be on the horizon.

Table. Ongoing Studies of Tipifarnib

 

References

  1. Baines AT, Xu D, Der CJ. Inhibition of Ras for cancer treatment: the search continues. Future Med Chem. 2011;3(14):1787-1808. doi: 10.4155/fmc.11.121.
  2. Klochkov SG, Neganovaa ME, Yarla NS, et al. Implications of farnesyltransferase and its inhibitors as a promising strategy for cancer therapy [published online October 31, 2017]. Semin Canc Biol. doi: 10.1016/j.semcancer.2017.10.010.
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  4. Agarwal R, Liebe S, Turski ML, et al; Pan-Cancer Working Group. Targeted therapy for genetic cancer syndromes: Fanconi anemia, medullary thyroid cancer, tuberous sclerosis, and RASopathies. Discov Med. 2015;19(103):101-108. ncbi.nlm.nih.gov/pubmed/25725224.
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  6. Chen X, Makarewicz JM, Knauf JA, Johnson LK, Fagin JA. Transformation by Hras(G12V) is consistently associated with mutant allele copy gains and is reversed by farnesyl transferase inhibition. Oncogene. 2014;33(47):5442­5449. doi: 10.1038/onc.2013.489.
  7. Ho A, Chau N, Wong D, et al. Preliminary results from a phase 2 proof of concept trial of tipifarnib in tumors with HRAS mutations. Presented at: 2017 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; October 26-30, 2017; Philadelphia, PA. Abstract LBA10. mct.aacrjournals.org/content/17/1_Supplement/LB-A10.
  8. Astor L. Activity seen with tipifarnib in HRAS-Mutant HNSCC in Proof-of-Concept Study. Targeted Oncology website. Targetedonc.com/link/182. Published December 27, 2017. Accessed March 2, 2018.
  9. Gualberto A, Scholz C, Mishra V, Janes MR, Kessler L, Raza A. The CXCL12/CXCR4 pathway as a potential target of tipifarnib in acute myeloid leukemia and myelodysplastic syndromes. Presented at: 2017 American Society of Hematology Annual Meeting; December 9-12, 2017; San Diego, CA. Abstract 3957. bloodjournal.org/content/130/Suppl_1/3957.
  10. Teicher BA, Fricker SP. CXCL12 (SDF-1)/CXCR4 pathway in cancer. Clin Cancer Res. 2010;16(11):2927-2931. doi: 10.1158/1078-0432.CCR-09-2329.
  11. Erba HP, Othus M, Walter RB, et al. Four different regimens of farnesyltransferase inhibitor tipifarnib in older, untreated acute myeloid leukemia patients: North American Intergroup phase II study SWOG S0432. Leuk Res. 2014;38(3):329-333. doi: 10.1016/j.leukres.2013.12.001.
  12. Kura Oncology provides regulatory update on tipifarnib and reports fourth quarter and full year 2017 financial results [press release]. San Diego, CA: Kura Oncology, Inc; March 12, 2018. ir.kuraoncology.com/news-releases/news-release-details/kura-oncology-provides-regulatory-update-tipifarnib-and-reports. Accessed April 5, 2018.
  13. Gordon LB, Massaro J, D'Agostino RB Sr, et al; Progeria Clinical Trials Collaborative. Impact of farnesylation inhibitors on survival in Hutchinson-Gilford progeria syndrome. Circulation. 2014;130(1):27-34. doi: 10.1161/CIRCULATIONAHA.113.008285.

 



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