About

Professor Stephen Howell is a researcher at UC San Diego with a focus on developing novel drugs and drug delivery systems for cancer treatment. His work emphasizes understanding the molecular and genetic mechanisms underlying drug resistance, particularly in ovarian cancer. Howell has contributed significantly to the early pharmacokinetic studies and clinical trials involving intraperitoneal chemotherapy for ovarian cancer, and his laboratory has advanced the understanding of how platinum-containing drugs interact with ovarian cancer cells, including their entry, trafficking, and exit, as well as mechanisms of resistance. His educational background includes a BA from the University of Chicago and an MD from Harvard Medical School, followed by extensive training at Massachusetts General Hospital, the Laboratory of Cell Biology at NCI, and Dana Farber Cancer Institute. Howell's research activities are supported by numerous grants, and he has been involved in various projects related to DNA adduct detection, platinum drug pharmacology, and cancer drug development. His work has led to important insights into cisplatin resistance pathways, the role of copper export pathways, and the molecular pharmacology of platinum drugs, contributing to the broader field of cancer therapeutics.

Research topics

• Medicine
• Chemistry
• Biology
• Cancer research
• Pharmacology

Selected publications

• Giant Outer Transiting Exoplanet Mass (GOT’EM) survey

  Astronomy and Astrophysics · 2026-02-04

  articleOpen access

  We present the characterisation of the TOI-6041 system, a bright ( V = 9.84 ± 0.03) G7-type star hosting at least two planets. The inner planet, TOI-6041 b, is a warm Neptune with a radius of 4.55 −0.17 +0.18 R ⊕ , initially identified as a single-transit event in TESS photometry. Subsequent observations with TESS and CHEOPS revealed additional transits, enabling the determination of its 26.04945 −0.00034 +0.00033 orbital period and the detection of significant transit-timing variations (TTVs), exhibiting a peak-to-peak amplitude of about 1 hour. Radial-velocity (RV) measurements obtained with the APF spectrographs allowed us to place a 3 σ upper mass limit of 28.9 M ⊕ on TOI-6041 b. In addition, the RV data reveal a second companion, TOI-6041 c, on an 88 d orbit, with a minimum mass of 0.25 M Jup . A preliminary TTV analysis suggested that the observed variations could be caused by gravitational perturbations from planet c; however, reproducing the observed amplitudes requires a relatively high eccentricity of about 0.3 for that planet. Our dynamical stability analysis indicates that such a configuration is dynamically viable and places a 1 σ upper limit on the mass of TOI-6041 c at 0.8 M Jup . An alternative is the presence of a third, low-mass planet located between planets b and c, or on an inner orbit relative to planet b – particularly near a mean-motion resonance with planet b – which could account for the observed variations. These findings remain tentative, and further RV and photometric observations are essential in to better constrain the mass of planet b and to refine the TTV modeling, thereby improving our understanding of the system’s dynamical architecture.

  PublisherDOI

• Suppl Figure 8 from Preclinical Development of Tuspetinib for the Treatment of Acute Myeloid Leukemia

  2025-05-13

  preprintOpen accessSenior author

  <p>Supplementary Figure 8</p>

  PublisherDOI

• Supplementary Tables from Preclinical Development of Tuspetinib for the Treatment of Acute Myeloid Leukemia

  2025-05-13

  supplementary-materialsOpen accessSenior author

  <p>Supplementary Table file to be published with manuscript</p>

  PublisherDOI

• Suppl Figure 4 from Preclinical Development of Tuspetinib for the Treatment of Acute Myeloid Leukemia

  2025-04-29

  preprintOpen accessSenior author

  <p>Supplementary Figure 4</p>

  PublisherDOI

• Suppl Figure 6 from Preclinical Development of Tuspetinib for the Treatment of Acute Myeloid Leukemia

  2025-05-13

  preprintOpen accessSenior author

  <p>Supplementary Figure 6</p>

  PublisherDOI

• Suppl Figure 8 from Preclinical Development of Tuspetinib for the Treatment of Acute Myeloid Leukemia

  2025-04-29

  preprintOpen accessSenior author

  <p>Supplementary Figure 8</p>

  PublisherDOI

• Suppl Figure 1 from Preclinical Development of Tuspetinib for the Treatment of Acute Myeloid Leukemia

  2025-04-29

  preprintOpen accessSenior author

  <p>Supplementary Figure 1</p>

  PublisherDOI

• Suppl Figure 5 from Preclinical Development of Tuspetinib for the Treatment of Acute Myeloid Leukemia

  2025-04-29

  preprintOpen accessSenior author

  <p>Supplementary Figure 5</p>

  PublisherDOI

• Abstract 1806: Cymirafen: A protein-drug conjugate that target LGR4/LGR5/LGR6-positive cancer stem cells

  Cancer Research · 2025-04-21

  articleSenior author

  Abstract INTRODUCTION: Cancer stem cells (CSC) are often drug-resistant and the source of recurrence; their destruction is a major therapeutic goal. LGR4/LGR5/LGR6 mark active stem cells and highly expressed in many solid cancers. Cymirafen consists of a human IgG1 Fc domain fused to the receptor-binding domains of RSPO1. The sortase reaction is used to site-specifically conjugate cleavable Gly3-val/cit-PAB-MMAE linkers to the C-terminal ends of the two chains through the formation of a highly stable peptide bond. We report here pre-IND studies that support the further development of cymirafen. METHODS: The protein component of cymirafen is constitutively produced by a stable CHO-K1 clone. Kd values were determined by ELISA using recombinant human and cynomolgus LGR5-His. In vitro growth rate inhibition assays used the CCK8 reagent. CDX models used SC implantation. Plasma cymirafen was measured by ELISA using antibodies to different RSPO1 epitopes for capture and detection. Free MMAE in plasma was determined by LC-MS/MS. RESULTS: Cymirafen binds to human and cynomolgus LGR5 with Kd of 0.27 and 0.38 nM, respectively. Its DAR is in the range 1.8-2.0. Across a panel of human cancer cell lines of multiple types, 76% had an IC50 of <10 nM, and in 36% IC50 was <5 nM. Against pairs of isogenic LGR5-low and LGR5-high OVCAR8 and HEK293 cells, cymirafen exhibited a 1.5 log differential IC50 in vitro. When grown as CDX, cymirafen was >2-fold more effective against OVCAR8/LGR5 than OVCAR8/EV. On a dose schedule of 85 mg/kg q7dx4, cymirafen was well tolerated in mice and active in CDX models of multiple types of cancer (colon, gastric, ovarian, neuroblastoma). Only 0.001, 0.002 and 0.013% of the MMAE was released from cymirafen in human, rat and cynomolgus plasma during 96 h at 37oC. MTD in mice is ∼128 mg/kg. A dose-ranging study in rats identified a single dose STD10 of 75 mg/kg. Serum chemistries disclosed no organ dysfunction. Adverse events were limited to dose-related neutropenia > thrombocytopenia with recovery by two weeks at all doses. Initial and terminal plasma half-lives were 0.8 and 21.5 h; PK was close to linear over the range of 30 - 75 mg/kg. In SKNAS CDX tumors, cymirafen peaked at 4 h and remained above the IC50 value for this tumor for ∼24 h. CONCLUSIONS: Cymirafen targets tumors with increased levels of LGR4, LGR5 and potentially LGR6, and co-receptors RNF43 and ZNRF3; an ADC can target only one receptor at a time. This favors greater control of drug resistance and recurrence. Unlike MMAE ADCs with long half-lives and cumulative toxicity, cymirafen delivers MMAE to tumors at high concentrations over a shorter period of time. It has a much higher normalized MMAE content than MMAE-containing ADCs. This permits administration of much higher doses on a well-tolerated weekly schedule. These features distinguish cymirafen from all MMAE ADCs and support its further development as a stem cell-targeted therapeutic. Citation Format: Maria Carmen Mulero Roig, Sukshala A. Jadhav, Willie Pi, Owen Tai, Stephen B. Howell. Cymirafen: A protein-drug conjugate that target LGR4/LGR5/LGR6-positive cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1806.

  PublisherDOI

• Figure 6 from Preclinical Development of Tuspetinib for the Treatment of Acute Myeloid Leukemia

  2025-01-13

  preprintOpen accessSenior author

  <p>Effect of NRAS<sup>G12D</sup> expression in MV-4-11 clones on sensitivity to (<b>A</b>) TUS and (<b>B</b>) VEN (data are mean ± SEM from three-independent experiments). <b>C,</b> Antitumor activity of TUS, belvarafenib, and the combination of both in mice bearing MV-4-11 NRAS<sup>G12D</sup> subcutaneous tumors (drugs were given once daily for 15 days via oral gavage; data are presented as mean ± SEM).</p>

  PublisherDOI

Recent grants

• NIH Grant R01CA069004

  NIH · $610k · 1999

• UCSD Cancer Center Training Program in Drug Development

  NIH · $9.8M · 2006–2027

• NIH Grant R01CA152185

  NIH · $1.5M · 2015

• NIH Grant R21CA177519

  NIH · $667k · 2017

• NIH Grant R55CA055725

  NIH · $100k · 1994

Frequent coauthors

• William G. Rice

  Aptose Biosciences (United States)

  70 shared

• Cheng‐Yu Tsai

  66 shared

• Roohangiz Safaei

  University of California, San Diego

  60 shared

• Alison K. Holzer

  50 shared

• Andrea Local

  48 shared

• Hongying Zhang

  47 shared

• Xinjian Lin

  Fujian Medical University

  46 shared

• Gerald Manorek

  Moores Cancer Center

  37 shared